Indole acetic acids exhibiting CRTH2 receptor antagonism and uses thereof

ABSTRACT

The invention relates to indole acetic acid compounds which function as antagonists of the CRTH2 receptor. The invention also relates to the use of these compounds to inhibit the binding of prostaglandin D 2  and its metabolites or certain thromboxane metabolites to the CRTH2 receptor and to treat disorders responsive to such inhibition.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of medicinal chemistry. In particular,the invention relates to indole acetic acid compounds which function asantagonists of the CRTH2 receptor. The invention also relates to the useof these compounds to inhibit the binding of prostaglandin D₂ and itsmetabolites to the CRTH2 receptor and to treat disorders responsive tosuch inhibition.

2. Related Art

The Chemoattractant Receptor-homologous molecule expressed on T-Helpertype 2 cells (CRTH2) receptor binds prostaglandin D₂ (PGD₂) and itsmetabolites. Efforts have been made to inhibit the binding of PGD₂ andother ligands to the CRTH2 receptor in order to treat disorders anddiseases related to excess activation of CRTH2.

Elevated PGD₂ is thought to play a causative role in both asthma andatopic dermatitis. For example, PGD₂ is one of the major prostanoidsreleased by mast cells in the asthmatic lung and this molecule is foundat high levels in the bronchial fluid of asthmatics (Liu et al., Am.Rev. Respir. Dis. 142:126 (1990)). Evidence of a role of PGD₂ in asthmais provided by a recent publication examining the effects ofoverexpression of prostaglandin D synthase on induction of allergicasthma in transgenic mice (Fujitani, J. Immunol. 168:443 (2002)). Afterallergen challenge, these animals had increased PGD₂ in the lungs, andthe number of Th2 cells and eosinophils were greatly elevated relativeto non-transgenic animals. These results are consistent with PGD₂ beinga primary chemotactic agent in the recruitment of inflammatory cellsduring allergic asthma.

PGD₂ can bind to two G-protein coupled receptors, DP (Boie et al., J.Biol. Chem. 270:18910 (1995)) and CRTH2 (Nagata et al., J. Immunol.162:1278 (1999); Hirai et al., J. Exp. Med. 193:255 (2001)). The latterreceptor might play a particularly important role in diseases such asasthma and atopic dermatitis that are characterized by Th2 cellinvolvement, since Th2 cell chemotaxis in response to PGD₂ appears to bemediated by CRTH2 (Hirai et al., above). Moreover, eosinophils, themajor inflammatory cell type seen in asthmatic lungs, show aCRTH2-mediated chemotactic response to PGD₂ (Hirai et al.) and certainthromboxane metabolites (Bohm et al., J. Biol. Chem. 279:7663 (2004)).

WO 03/066046 discloses compounds of the following formula which areactive at the CRTH2 receptor:

wherein:

-   R¹ is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy;-   R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy;-   R³ is hydrogen, C₁₋₆ alkyl;-   R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, thio C₁₋₆ alkyl; and-   X is N or CH.

WO 03/66047 discloses compounds of the following formula which areactive at the CRTH2 receptor:

wherein:

-   R¹ is a 1,3-benzothiazole group optionally substituted by halogen,    C₁₋₆ alkyl,-   C₁₋₆ alkoxy, or a group of Formula (A) or (B):

-   where R⁴ and R⁵ are independently halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,    phenoxy optionally substituted by halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy,

-   where one of X and Y is nitrogen and the other is nitrogen, oxygen,    or sulfur and R⁶ is phenyl optionally substituted by halogen, C₁₋₆    alkyl, C₁₋₆ alkoxy;-   R² is hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy; and-   R³ is hydrogen, C₁₋₆ alkyl.

WO 03/101961 discloses compounds of the following formula which areactive at the CRTH2 receptor:

wherein:

-   R¹ is hydrogen, halogen, CN, nitro, SO₂R⁴, OH, OR⁴, S(O)_(x)R⁴,    SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶, aryl (optionally substituted by chlorine    or fluorine), C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₁-C₆ alkyl, the    latter three groups being optionally substituted by one or more    substituents independently selected from halogen, OR⁸ and NR⁵R⁶,    S(O)_(x)R⁷ where x is 0, 1, or 2;-   R² is hydrogen, halogen, CN, SO₂R⁴ or CONR⁵R⁶, CH₂OH, CH₂OR⁴or C₁-C₇    alkyl, the latter group being optionally substituted by one or more    substituents independently selected from halogen atoms, OR⁸ and    NR⁵R⁶, S(O)_(x)R⁷ where x is 0, 1, or 2;-   R³ is aryl or heteroaryl each of which is optionally substituted by    one or more substituents independently selected from hydrogen,    halogen, CN, nitro, OH, SO₂R⁴, OR⁴, SR⁴, SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶,    NR⁵R⁶, NHCOR⁴, NHSO₂R⁴, NHCO₂R⁴, NR⁷SO₂R⁴, NR⁷CO₂R⁴, C₂-C₆ alkenyl,    C₂-C₆ alkynyl or C₁-C₆ alkyl, the latter three groups being    optionally substituted by one or more substituents independently    selected from halogen, OR⁸ and NR⁵R⁶, S(O)_(x)R⁷ where x is 0, 1, or    2;-   R⁴ represents aryl, heteroaryl, or C₁-C₆ alkyl all of which may be    optionally substituted by one or more substituents independently    selected from halogen atoms, aryl, heteroaryl, OR¹⁰, OH, NR¹¹R¹²,    S(O)_(x)R¹³ (where x=0, 1, or 2), CONR¹⁴R¹⁵, NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵,    NR¹⁴SO₂R¹⁵, CN, nitro;-   R⁵ and R⁶ independently represent a hydrogen atom, a C₁-C₆ alkyl    group, or an aryl, or a heteroaryl, the latter three of which may be    optionally substituted by one or more substituents independently    selected from halogen atoms, aryl, OR⁸ and NR¹⁴R¹⁵, CONR¹⁴R¹⁵,    NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵, NR¹⁴SO₂R¹⁵, CN, nitro; or-   R⁵ and R⁶ together with the nitrogen atom to which they are attached    can form a 3-8 membered saturated heterocyclic ring optionally    containing one or more atoms selected from O, S(O)_(x) where x=0, 1,    or 2, NR¹⁶, and itself optionally substituted by C₁-C₃ alkyl;-   R⁷ and R¹³ independently represent a C₁-C₆ alkyl, an aryl or a    heteroaryl group, all of which may be optionally substituted by    halogen atoms;-   R⁸ represents a hydrogen atom, C(O)R⁹, C₁-C₆ alkyl, an aryl or a    heteroaryl group, all of which may be optionally substituted by    halogen atoms;-   each of R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, independently represents a    hydrogen atom, C₁-C₆ alkyl, an aryl or heteroaryl group (all of    which may be optionally substituted by halogen atoms); and-   R¹⁶ is hydrogen, C₁-C₄ alkyl, COC₁-C₄ alkyl, COYC₁-C₄ alkyl where Y    is O or NR⁷,-   provided that when R¹ is hydrogen and R² is methyl, then R³ is not    2-nitrophenyl.

WO 03/101981 discloses compounds of the following formula which areactive at the CRTH2 receptor:

wherein:

-   R¹ is hydrogen, halogen, CN, nitro, SO₂R⁴, OH, OR⁴, SR⁴, SOR⁴,    SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶, NR⁹SO₂R⁴, NR⁹CO₂R⁴, NR⁹COR⁴, heteroaryl,    aryl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₁-C₆ alkyl, the latter five    groups being optionally substituted by one or more substituents    independently selected from halogen,-   OR⁸ and NR⁵R⁶, S(O)_(x)R⁷ where x is 0, 1, or 2;-   R² is hydrogen, halogen, CN, SO₂R⁴ or CONR⁵R⁶, CH₂OH, CH₂OR⁴ or    C₁-C₇ alkyl, the latter group being optionally substituted by one or    more substituents independently selected from halogen atoms, OR⁸ and    NR⁵R⁶, S(O)_(x)R⁷ where x is 0, 1, or 2;-   R³ is aryl or heteroaryl each of which is optionally substituted by    one or more substituents independently selected from hydrogen,    halogen, CN, nitro, OH, SO₂R⁴, OR⁴, SR⁴, SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶,    NR⁵R⁶, NR⁹SO₂R⁴, NR⁹CO₂R⁴, NR⁹CO₂H, NR⁹COR⁴, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₁-C₆ alkyl, the latter three groups being optionally    substituted by one or more substituents independently selected from    halogen atoms, OR⁸ and NR⁵R⁶, S(O)_(x)R⁷ where x is 0, 1,or 2;-   with the proviso that R³ cannot be phenyl or substituted phenyl;-   R⁴ represents aryl, heteroaryl, or C₁-C₆ alkyl all of which may be    optionally substituted by one or more substituents independently    selected from halogen atoms, aryl, heteroaryl, OR¹⁰, and NR¹¹R¹²,    S(O)_(x)R¹³ (where x=0, 1, or 2), CONR¹⁴R¹⁵, NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵,    NR¹⁴SO₂R¹⁵;-   R⁵ and R⁶ independently represent a hydrogen atom, a C₁-C₆ alkyl    group, or an aryl, or a heteroaryl, the latter three of which may be    optionally substituted by one or more substituents independently    selected from halogen atoms, aryl, OR⁸ and NR¹⁴R¹⁵, CONR¹⁴R¹⁵,    NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵, NR¹⁴SO₂R¹⁵; or-   R⁵ and R⁶ together with the nitrogen atom to which they are attached    can form a 3-8 membered saturated heterocyclic ring optionally    containing one or more atoms selected from O, S(O)_(x) where x=0, 1,    or 2, NR¹⁶, and itself optionally substituted by C₁-C₃ alkyl;-   R⁷ and R¹³ independently represent a C₁-C₆ alkyl, an aryl or a    heteroaryl group, all of which may be optionally substituted by    halogen atoms;-   R⁸ represents a hydrogen atom, C(O)R⁹, C₁-C₆ alkyl, an aryl or a    heteroaryl group, all of which may be optionally substituted by    halogen atoms or an aryl group;-   each of R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, independently represents a    hydrogen atom, C₁-C₆ alkyl, an aryl or heteroaryl group (all of    which may be optionally substituted by halogen atoms); and-   R¹⁶ is hydrogen, C₁-C₄ alkyl, COC₁-C₄ alkyl, COYC₁-C₄ alkyl where Y    is O or NR⁷.

WO 2004/007451 discloses compounds of the following formula which areactive at the CRTH2 receptor:

wherein:

-   n represents 1 or 2;-   R¹ is one or more substituents independently selected from halogen,    CN, nitro, SO₂R⁴, OR⁴, SR⁴, SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶, NR⁵R⁶,    NR⁹SO₂R⁴, NR⁹CO₂R⁴, NR⁹COR⁴, aryl, heteroaryl, C₂-C₆ alkenyl, C₂-C₆    alkynyl or C₁-C₆ alkyl, the latter five groups being optionally    substituted by one or more substituents independently selected from    halogen, OR⁷ and NR⁸R⁹, S(O)_(x)R⁷ where x is 0, 1, or 2;-   R² is hydrogen, halogen, CN, SO₂R⁴ or CONR⁵R⁶, COR⁴ or C₁-C₇ alkyl,    the latter group being optionally substituted by one or more    substituents independently selected from halogen atoms, OR⁸ and    NR⁵R⁶, S(O)_(x)R⁷ where x is 0, 1, or 2;-   R³ is aryl or a 5-7 membered heteroaryl ring containing one or more    heteroatoms selected from N, S, and O, each of which is optionally    substituted by one or more substituents independently selected from    halogen, CN, nitro, SO₂R⁴, OH, OR⁴, SR⁴, SOR⁴, SO₂NR⁵R⁶, CONR⁵R⁶,    NR⁵R⁶, NR⁹SO₂R⁴, NR⁹CO₂R⁴, NR⁹COR⁴, C₂-C₆ alkenyl, C₂-C₆ alkynyl    C₁-C₆ alkyl, the latter three groups being optionally substituted by    one or more substituents independently selected from halogen atoms,    OR⁷ and NR⁵R⁶, S(O)_(x)R⁷ where x is 0, 1, or 2;-   R⁴ represents aryl, heteroaryl, or C₁-C₆ alkyl all of which may be    optionally substituted by one or more substituents independently    selected from halogen atoms, aryl, heteroaryl, OR¹⁰, and NR¹¹R¹²,    S(O)_(x)R¹³ (where x=0, 1, or 2), CONR¹⁴R¹⁵, NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵,    NR¹⁴SO₂R¹⁵, CN, nitro;-   R⁵ and R⁶ independently represent a hydrogen atom, a C₁-C₆ alkyl    group, an aryl, or a heteroaryl, the latter three of which may be    optionally substituted by one or more substituents independently    selected from halogen atoms, aryl, OR¹³ and NR¹⁴R¹⁵, CONR¹⁴ R¹⁵,    NR¹⁴COR¹⁵, SO₂NR¹⁴R¹⁵, NR¹⁴SO₂R¹⁵, CN nitro; or-   R⁵ and R⁶ together with the nitrogen atom to which they are attached    can form a 3-8 membered saturated heterocyclic ring optionally    containing one or more atoms selected from O, S(O)_(x) where x=0, 1,    or 2, NR¹⁶, and the ring itself optionally substituted by C₁-C₃    alkyl;-   R⁷ and R¹³ independently represent a C₁-C₆ alkyl, an aryl or a    heteroaryl group, all of which may be optionally substituted by    halogen atoms;-   R⁸ represents a hydrogen atom, C(O)R⁹, C₁-C₆ alkyl (optionally    substituted by halogen atoms, aryl or heteroaryl groups, both of    which may also be optionally substituted by one or more fluorine    atoms), an aryl or heteroaryl group, which may be optionally    substituted by one or more halogen atoms;-   each of R⁹, R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, independently represents a    hydrogen atom, C₁-C₆ alkyl, an aryl or a heteroaryl group (all of    which may be optionally substituted by halogen atoms); and-   R¹⁶ is hydrogen, C₁-C₄ alkyl, COC₁-C₄ alkyl, C(O)YC₁-C₄ alkyl, Y is    O or NR⁷.

WO 02/060438 discloses compounds of the following formula that can beused as integrin antagonists:

-   wherein R¹, R², R³, R⁴, and R⁵ independently represent hydrogen,    halogen, alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;-   R⁶, R⁷, R⁸, and R⁹ independently represent hydrogen, alkyl,    hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,    carboxyalkyl, aryl, or aralkyl;-   or R⁶ and R⁷ are taken together to form —(CH₂)_(p)—, where p is 2-8,    while R⁸ and R⁹ are defined as above; or R⁸ and R⁹ are taken    together to form —(CH₂)_(q)—, where q is 2-8, while R⁶ and R⁷ are    defined as above; or R⁶ and R⁸ are taken together to form    —(CH₂)_(r)—, while r is zero (a bond), 1, or 2, while R⁷ and R⁹ are    defined as above;-   X represents oxygen, sulfur, —CH₂—, —NH—, —(C═O)NH—, or —NH(C═O)—;-   n is from 0 to 4;-   m is from 0 to 4;-   a is 0 or 1;-   D represents oxygen;-   V is 0 or 1;-   R¹⁰, R¹¹, R¹², and R¹³ independently represent: hydrogen; hydroxy;    alkyl; alkoxy; cycloalkyl; aryl, optionally substituted with one or    more of halogen, hydroxy, cyano, alkyl, aryl, alkoxy, haloalkyl,    arylalkyl, arylalkoxy, aryloxy, alkylsulfonyl, alkylsulfinyl,    alkoxyarylalkyl, monoalkylamino, dialkylamino, aminoalkyl,    monoalkylaminoalkyl, dialkylaminoalkyl, alkanoyl; monoalkylamino;    dialkylamino; aminoalkyl; monoalkylaminoalkyl; dialkylaminoalkyl;    alkanoyl; heteroaryl having 5-14 ring members, optionally    substituted with one or more of halogen, hydroxy, cyano, alkyl,    aryl, alkoxy, haloalkyl, arylalkyl, arylalkoxy, aryloxy,    alkylsulfonyl, alkylsulfinyl, alkoxyarylalkyl, monoalkylamino,    dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,    alkanoyl; or

-   wherein R¹⁷ and R¹⁸ together form —CH₂CH₂—O—, —O—CH₂CH₂—, —O—CH₂—O—,    or —O—CH₂CH₂—O—; or-   R¹⁰ and R¹² are taken together to form —(CH₂)_(s)—, wherein s is 0    (a bond) or 1 to 4, while R¹¹ and R¹³ are defined as above; or R¹⁰    and R¹² are taken together to form a double bond when i is 0 and k    is 1, while R¹¹ and R¹³ are as defined above; or R¹⁰ and R¹¹ are    taken together to form —(CH₂)_(t)—, wherein t is 2 to 8, while R¹²    and R¹³ are defined as above, or R¹² and R¹³ are taken together to    form —(CH₂)_(u)— wherein u is 2 to 8, while R¹⁰ and R¹¹ are defined    as above;-   i is from 0 to 4;-   j is from 0 to 4;-   k is 0 or 1;-   R¹⁴ is hydrogen or a functionality that acts as a prodrug;-   W is

-   wherein Y is —N— or —CH—;-   Z is —N— or —CH—;-   R¹⁵ is hydrogen, halogen, alkyl, aryl, or arylalkyl;-   R¹⁶ is hydrogen, alkyl, haloalkyl, or halogen;-   R¹⁹ and R²⁰ are independently hydrogen, halogen, or alkyl;-   R²⁷, R²⁸, R²⁹, R³⁰, and R³¹ are independently hydrogen, halogen,    alkyl, alkoxy or aryl; and-   o and p are independently 0, 1, or 2.

SUMMARY OF THE INVENTION

The present invention relates to indole acetic acid compounds that areuseful for inhibiting binding of endogenous ligands to the CRTH2receptor. In particular, the compounds of the present invention act asantagonists of the human CRTH2 receptor (hCRTH2). In one embodiment, theindole acetic acids are compounds of Formula I:

and pharmaceutically acceptable salts and prodrugs thereof, wherein:

-   the dotted lines are single or double bonds;-   X is C═O, S═O, or SO₂;-   Z is N or a covalent bond;-   R₁ is selected from the group consisting of H or optionally    substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀    alkylaryl, C₁₋₁₀ alkylheteroaryl, —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, —C₁₋₁₀    alkyl-O-aryl, —C₁₋₁₀ alkyl-O-heteroaryl, aryl, or heteroaryl;-   R₂, R_(2a), R₃ and R_(3a) are independently selected from the group    consisting of H, halogen, or C₁₋₁₀ alkyl, wherein R_(2a) and R_(3a)    exist only when the carbons to which they are attached are    saturated; or-   R₂ and R₃ form an optionally substituted saturated, unsaturated, or    aromatic 5- or 6-member ring; or-   R₂ and R_(2a) form an optionally substituted saturated 3-6 member    ring;-   R₄ is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, or halogen,    wherein R₄ exists only when the carbon to which it is attached is    saturated;-   R₅ is H, C₁₋₁₀ alkyl, perhaloalkyl (preferably CF₃), C₂₋₁₀ alkenyl,    C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀ alkylheteroaryl, aryl, or    heteroaryl, wherein said aryl or heteroaryl can be optionally    substituted with one or more substituents selected from C₁₋₁₀ alkyl,    halogen, C₁₋₁₀ alkoxy, or CN;-   R₆ is one or more H, halogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀    alkynyl, CN, OR₇, SR₇, aryl or heteroaryl groups; and-   R₇ is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, or    heteroaryl.

The invention relates to compounds represented by Formula I, which areantagonists of CRTH2. The invention relates to the use of the compoundsof the invention to inhibit binding of endogenous ligands, includingPGD₂ and its metabolites and certain thromboxane metabolites (such as11-dehydro-TXB₂ (Bohm et al., J. Biol. Chem. 279:7663 (2004)), to CRTH2.The compounds are useful for the treatment, amelioration, or preventionof disorders responsive to inhibition of binding to CRTH2, e.g.,disorders characterized by elevated levels of PGD₂ or its metabolites orcertain thromboxane metabolites. These disorders include, but are notlimited to, respiratory tract disorders (e.g., asthma, chronicobstructive pulmonary disease, rhinitis), bone and joint disorders(e.g., arthritis, Sjogren's syndrome), skin and eye disorders (e.g.,psoriasis, dermatitis, uveitis, conjunctivitis), gastrointestinal tractdisorders (e.g., colitis, celiac disease, Crohn's disease), central andperipheral nervous system disorders (e.g., Alzheimer's disease, multiplesclerosis, migraine, stroke), disorders of other tissues and systemicdisorders (e.g., atherosclerosis, AIDS, sepsis, ischemic/reperfusioninjury, hepatitis) and allograft rejection.

The present invention provides methods of blocking/antagonizing theCRTH2 receptor on a cell, comprising contacting the cell with a compoundof Formula I. The present invention also provides methods of treating,ameliorating, or preventing a disorder responsive toblocking/antagonizing the CRTH2 receptor in an animal, comprisingadministering to said animal a therapeutically effective amount of acompound of Formula I.

The present invention provides pharmaceutical compositions comprising acompound of Formula I in a therapeutically effective amount to inhibitbinding to the CRTH2 receptor. The compositions may further compriseother therapeutic agents.

The invention further provides kits comprising a compound of Formula Iand instructions for administering the compound to an animal. The kitsmay optionally contain other therapeutic agents.

The invention also provides methods of making compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds represented by Formula I,which are antagonists of the CRTH2 receptor and function as inhibitorsof the binding of endogenous ligands to the CRTH2 receptor. Byinhibiting the binding of endogenous ligands such as PGD₂ and itsmetabolites, these compounds at least partially inhibit the effects ofthe endogenous ligands in an animal. Therefore, the invention relates tomethods of inhibiting the binding of endogenous ligands to the CRTH2receptor on a cell, comprising contacting the cell with a compound ofFormula I. The invention further relates to methods of treating,ameliorating, or preventing disorders in an animal that are responsiveto inhibition of the CRTH2 receptor comprising administering to theanimal a compound of Formula I. Such disorders include thosecharacterized by elevated levels of PGD₂ or its metabolites or certainthromboxane metabolites.

The term “CRTH2 receptor,” as used herein, refers to any known member ofthe CRTH2 receptor family, including, but not limited to, hCRTH2.

The term “elevated levels of PGD₂ or its metabolites or certainthromboxane metabolites,” as used herein, refers to an elevated level(e.g., aberrant level) of these molecules in biological tissue or fluidas compared to similar corresponding non-pathological tissue or fluidcontaining basal levels of PGD₂ or its metabolites or thromboxanes andmetabolites.

The term “other therapeutic agents,” as used herein, refers to anytherapeutic agent that has been used, is currently used, or is known tobe useful for treating, ameliorating, or preventing a disorderencompassed by the present invention. For example, agents used to treatasthma and rhinitis include steroids, β2-receptor agonists andleukotriene receptor antagonists.

The term “prodrug,” as used herein, refers to a pharmacologicallyinactive derivative of a parent “drug” molecule that requiresbiotransformation (e.g., either spontaneous or enzymatic) within thetarget physiological system to release or convert the prodrug into theactive drug. Prodrugs are designed to overcome problems associated withstability, toxicity, lack of specificity, or limited bioavailability.Exemplary prodrugs comprise an active drug molecule itself and achemical masking group (e.g., a group that reversibly suppresses theactivity of the drug). Some preferred prodrugs are variations orderivatives of compounds that have groups cleavable under metabolicconditions. Exemplary prodrugs become pharmaceutically active in vivo orin vitro when they undergo solvolysis under physiological conditions orundergo enzymatic degradation or other biochemical transformation (e.g.,phosphorylation, hydrogenation, dehydrogenation, glycosylation).Prodrugs often offer advantages of solubility, tissue compatibility, ordelayed release in the mammalian organism. (See e.g., Bundgard, Designof Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam (1985); and Silverman,The Organic Chemistry of Drug Design and Drug Action, pp. 352-401,Academic Press, San Diego, Calif. (1992)). Common prodrugs include acidderivatives such as esters prepared by reaction of parent acids with asuitable alcohol (e.g., a lower alkanol), amides prepared by reaction ofthe parent acid compound with an amine, or basic groups reacted to forman acylated base derivative (e.g., a lower alkylamide).

The term “pharmaceutically acceptable salt,” as used herein, refers toany salt (e.g., obtained by reaction with an acid or a base) of acompound of the present invention that is physiologically tolerated inthe target animal (e.g., a mammal). Salts of the compounds of thepresent invention may be derived from inorganic or organic acids andbases. Examples of acids include, but are not limited to, hydrochloric,hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric,glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric,acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic,malonic, sulfonic, naphthalene-2-sulfonic, benzenesulfonic acid, and thelike.

Examples of bases include, but are not limited to, alkali metal (e.g.,sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide,iodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, palnoate, pectinate,persulfate, phenylpropionate, picrate, pivalate, propionate, succinate,tartrate, thiocyanate, tosylate, undecanoate, and the like. Otherexamples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like. For therapeutic use,salts of the compounds of the present invention are contemplated asbeing pharmaceutically acceptable. However, salts of acids and basesthat are non-pharmaceutically acceptable may also find use, for example,in the preparation or purification of a pharmaceutically acceptablecompound.

The term “therapeutically effective amount,” as used herein, refers tothat amount of the therapeutic agent sufficient to result inamelioration of one or more symptoms of a disorder, or preventadvancement of a disorder, or cause regression of the disorder. Forexample, with respect to the treatment of asthma, a therapeuticallyeffective amount preferably refers to the amount of a therapeutic agentthat increases peak air flow by at least 5%, preferably at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 100%.

The terms “prevent,” “preventing,” and “prevention,” as used herein,refer to a decrease in the occurrence of pathological cells (e.g., Th₂cells, eosinophils, etc.) or a pathological condition (e.g., constrictedairways) in an animal. The prevention may be complete, e.g., the totalabsence of pathological cells or a pathological condition in an animal.The prevention may also be partial, such that the occurrence ofpathological cells or a pathological condition in an animal is less thanthat which would have occurred without the present invention.

The compounds of the present invention are compounds having Formula I:

and pharmaceutically acceptable salts and prodrugs thereof, wherein:

-   the dotted lines are single or double bonds;-   X is C═O, S═O, or SO₂;-   Z is N or a covalent bond;-   R₁ is selected from the group consisting of H or optionally    substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀    alkylaryl, C₁₋₁₀ alkylheteroaryl, —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, —C₁₋₁₀    alkyl-O-aryl, —C₁₋₁₀ alkyl-O-heteroaryl, aryl, or heteroaryl;-   R₂, R_(2a), R₃ and R_(3a) are independently selected from the group    consisting of H, halogen, or C₁₋₁₀ alkyl, wherein R_(2a) and R_(3a)    exist only when the carbons to which they are attached are    saturated; or-   R₂ and R₃ form an optionally substituted saturated, unsaturated, or    aromatic 5- or 6-member ring; or-   R₂ and R_(2a) form an optionally substituted saturated 3-6 member    ring;-   R₄ is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, or halogen,    wherein R₄ exists only when the carbon to which it is attached is    saturated;-   R₅ is H, C₁₋₁₀ alkyl, perhaloalkyl (preferably CF₃), C₂-₁₀ alkenyl,    C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀ alkylheteroaryl, aryl, or    heteroaryl, wherein said aryl or heteroaryl can be optionally    substituted with one or more substituents selected from C₁₋₁₀ alkyl,    halogen, C₁₋₁₀ alkoxy, or CN;-   R₆ is one or more H, halogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀    alkynyl, CN, OR₇, SR₇, aryl or heteroaryl groups; and-   R₇ is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, or    heteroaryl.

In particular embodiments, the compounds of the present invention arecompounds having Formula II:

and pharmaceutically acceptable salts and prodrugs thereof, whereinR₁—R₇ are as defined above.

In particular embodiments, the compounds of the present invention arecompounds having Formula III:

and pharmaceutically acceptable salts and prodrugs thereof, whereinR₁—R₇ are as defined above.

In particular embodiments, the compounds of the present invention arecompounds having Formula IV:

and pharmaceutically acceptable salts and prodrugs thereof, whereinR₁—R₇ are as defined above.

In particular embodiments, the compounds of the present invention arecompounds having Formula V:

and pharmaceutically acceptable salts and prodrugs thereof, whereinR₁—R₇ are as defined above.

Useful alkyl groups include straight-chained or branched C₁₋₁₀ alkylgroups, especially methyl, ethyl, propyl, isopropyl, t-butyl, sec-butyl,3-pentyl, adamantyl, norbomyl, and 3-hexyl groups, as well as C₁₋₁₀cycloalkyl groups, e.g., cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. Lower alkyl groups are C₁₋₆ alkyl groups.

Useful alkenyl groups include straight-chained or branched C₂₋₁₀ alkylgroups, especially ethenyl, propenyl, isopropenyl, butenyl, isobutenyl,and hexenyl.

Useful alkynyl groups include straight-chained or branched C₂₋₁₀ alkynylgroups, especially ethynyl, propynyl, butynyl, isobutynyl, and hexynyl.

Useful acyloxyl groups are any C₁₋₆ acyl (alkanoyl) attached to an oxy(—O—) group, e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy,pentanoyloxy, hexanoyloxy and the like.

Useful aryl groups include C₆₋₁₄ aryl, especially phenyl, naphthyl,phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl,and fluorenyl groups.

Useful heteroaryl groups include thiazolyl, oxazolyl, thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, benzodioxinyl, benzothiazolyl,thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl,3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl,pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione,7-aminoisocoumarin, pyrido[1,2-a]pyrimidin-4-one,1,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, and2-oxobenzimidazolyl. Where the heteroaryl group contains a nitrogen atomin a ring, such nitrogen atom may be in the form of an N-oxide, e.g., apyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, and the like.

Optional substituents include one or more alkyl; halo; haloalkyl;haloalkoxy; cycloalkyl; hydroxy; cyano; aryl optionally substituted withone or more lower alkyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl,aryloxy, heteroaryl or heteroaryloxy groups; aryloxy optionallysubstituted with one or more lower alkyl, haloalkyl, alkoxy, haloalkoxy,aryl, or heteroaryl groups; carbamoyl optionally substituted with one ormore lower alkyl, halo, haloalkyl, alkoxy, haloalkoxy, aryl orheteroaryl groups; aralkyl, heteroaryl optionally substituted with oneor more lower alkyl, halo, haloalkyl, haloalkoxy, alkoxy, aryl, aryloxy,heteroaryl or heteroaryloxy groups; heteroaryloxy optionally substitutedwith one or more lower alkyl, haloalkyl, alkoxy, haloalkoxy, and arylgroups; alkoxy; alkoxycarbonyl; alkylthio; arylthio; amino; acyloxy;arylacyloxy optionally substituted with one or more lower alkyl,haloalkyl, alkoxy, haloalkoxy, and aryl groups; diphenylphosphinyloxyoptionally substituted with one or more lower alkyl, halo, haloalkyl,alkoxy, or haloalkoxy groups; heterocyclo optionally substituted withone or more lower alkyl, haloalkyl, alkoxy, haloalkoxy, and aryl groups;heterocycloalkoxy optionally substituted with one or more lower alkyl,haloalkyl, alkoxy, haloalkoxy, and aryl groups; partially unsaturatedheterocycloalkyl optionally substituted with one or more lower alkyl,haloalkyl, alkoxy, haloalkoxy, and aryl groups; or partially unsaturatedheterocycloalkyloxy optionally substituted with one or more lower alkyl,haloalkyl, alkoxy, haloalkoxy, and aryl groups.

Useful halo or halogen groups include fluorine, chlorine, bromine andiodine.

Useful arylalkyl groups or heteroarylalkyl groups include any of theabove-mentioned C-₁₋₁₀ alkyl groups substituted by any of theabove-mentioned C₆₋₁₄ aryl groups or heteroaryl groups. Useful valuesinclude benzyl, phenethyl and naphthylmethyl.

Useful arylacyloxyl groups or heteroarylacyloxyl groups include any ofthe aryl groups or heteroaryl groups mentioned above substituted on anyof the acyloxyl groups mentioned above, e.g., 2,6-dichlorobenzoyloxy,2,6-difluorobenzoyloxy and 2,6-di-(trifluoromethyl)-benzoyloxy groups.

Useful alkoxyl groups include oxygen substituted by one of the C₁₋₁₀alkyl groups mentioned above.

Useful arylalkoxyl groups or heteroarylalkoxyl groups include any of thearyl groups or heteroaryl groups mentioned above substituted on any ofthe alkoxyl groups mentioned above

Useful heterocyclic groups include tetrahydrofuranyl, pyranyl,piperidinyl, piperizinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl,indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl,chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.

Certain of the compounds of the present invention may exist asstereoisomers including optical isomers. The invention includes allstereoisomers and both the racemic mixtures of such stereoisomers aswell as the individual enantiomers that may be separated according tomethods that are well known to those of skill in the art.

The compounds of this invention may be prepared using methods known tothose of skill in the art. In one embodiment, the compounds may beprepared by general synthetic scheme 1:

-   wherein R₈ is H, halo, C₁₋₁₀ alkoxy, cyano, C₁₋₁₀ alkyl, C₂₋₁₀    alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀ alkylbeteroaryl,    —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, —C₁₋₁₀ alkyl-O-aryl, —C₁₋₁₀    alkyl-O-heteroaryl, aryl, or heteroaryl;-   Q is a halogen;-   X is a halogen; and-   Y is a protecting group, such as alkyl (e.g., t-butyl).

Indole benzothiadiazines may be prepared by Scheme 2:

-   wherein R₈ is H, halo, C₁₋₁₀ alkoxy, cyano, C₁₋₁₀ alkyl, C₂₋₁₀    alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀ alkyiheteroaryl,    —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, —C₁₋₁₀ alkyl-O-aryl, —C₁₋₁₀    alkyl-O-heteroaryl, aryl, or heteroaryl; and-   Y is a protecting group, such as alkyl (e.g., t-butyl).

Indole quinazolinones may be prepared by Scheme 3:

-   wherein R₈ is H, halo, C₁₋₁₀ alkoxy, cyano, C₁₋₁₀ alkyl, C₂₋₁₀    alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀ alkylheteroaryl,    —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, —C₁₋₁₀ alkyl-O-aryl, —C₁₋₁₀    alkyl-O-heteroaryl, aryl, or heteroaryl; and-   Y is a protecting group, such as alkyl (e.g., t-butyl).

Indole isoindolones may be prepared by Scheme 4:

-   wherein R₈ is H, halo, C₁₋₁₀ alkoxy, cyano, C₁₋₁₀ alkyl, C₂₋₁₀    alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀ alkylheteroaryl,    —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, —C₁₋₁₀ alkyl-O-aryl, —C₁₋₁₀    alkyl-O-heteroaryl, aryl, or heteroaryl; and-   Y is a protecting group, such as alkyl (e.g., t-butyl).

Alpha-methyl saccharin derivatives may be prepared by Scheme 5:

-   wherein Y is a protecting group, such as alkyl (e.g., t-butyl); and-   R₈ is H, halo, C₁₋₁₀ alkoxy, cyano, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,    C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀ alkylheteroaryl, —C₁₋₁₀    alkyl-O—C₁₋₁₀ alkyl, —C₁₋₁₀ alkyl-O-aryl, —C₁₋₁₀ alkyl-O-heteroaryl,    aryl, or heteroaryl.

Des-benzo saccharin derivatives may be prepared by Scheme 6:

wherein Y is a protecting group, such as alkyl (e.g., t-butyl).

Dihydro-pyridazinone derivatives may be prepared by Scheme 7:

In one embodiment, the invention relates to a method of preparing acompound having formula XII or XIII, comprising

-   a) halogenating a compound having formula VI with a halogenating    agent (e.g., SOCl₂) in a solvent or mixture of solvents (e.g.,    dioxane and dimethylformamide (DMF)) at elevated temperature (e.g.,    about 80-120° C.) for a sufficient time (e.g., overnight) to form a    compound having formula VII, where Q is a halogen (e.g., Cl), which    is then isolated (e.g., concentrated to dryness and recrystallized)    (see, e.g., U.S. Pat. No. 4,140,693);

-   b) condensing a compound having formula VII with an indole compound    VIII in the presence of a Lewis acid (e.g., AlCl₃) in a polar    solvent (e.g., 1,2-dichloroethane) at elevated temperature (e.g.,    about 65° C.) for a sufficient time (e.g., overnight) to form a    compound having formula IX, which is then isolated (e.g., the    reaction is cooled and quenched with water, filtered, washed, and    dried);

-   c) alkylating a compound having formula IX with a halogenated acetic    acid alkyl ester (e.g., t-butyl bromoacetate) in a solvent (e.g.,    DMF) in the presence of a base (e.g., K₂CO₃) at elevated temperature    (e.g., about 80-100° C.) for a sufficient time (e.g., several hours)    to form a compound having formula X, which is then isolated (e.g.,    extracted, dried, and concentrated);

-   d) reducing a compound having formula X with a reducing agent (e.g.,    NaBH₄) in a polar solvent (e.g., methanol) at about room temperature    to form a compound having formula XI, which is then isolated (e.g.,    quenched with an organic acid (e.g., acetic acid), extracted with an    organic solvent (e.g., dichloromethane (DCM)), dried and    concentrated);

-   e) deprotecting a compound having formula XI e.g., with an organic    acid (e.g., trifluoroacetic acid (TFA)) at about room temperature,    to form a compound having formula XII, which is then isolated (e.g.,    concentrated to dryness and purified by preparative liquid    chromatography/mass spectrometry (LCMS)); or

-   f) alkylating or arylating a compound having formula XI followed by    deprotecting to form a compound having formula XIII, which is then    isolated (e.g., concentrated to dryness and purified by LCMS).

In one embodiment, the invention relates to a method of preparing acompound having formula XII or XIII, comprising deprotecting a compoundhaving formula XI to form a compound having formula XII; or

alkylating or arylating a compound having formula XI followed bydeprotecting to form a compound having formula XIII.

In one embodiment, the invention relates to a method of preparing acompound having formula XIX or XX, comprising

-   a) condensing a compound having formula XIV with hydrazine e.g., in    a non-polar solvent (e.g., ether) at about room temperature followed    by an organic acid (e.g., acetic acid) to form a compound having    formula XV, which is then isolated (e.g., washed with water, dried,    and concentrated);

-   b) halogenating a compound having formula XV with a halogenating    agent (e.g., POCl₃) e.g., at elevated temperature (e.g., about    80-100° C.) for a sufficient time (e.g., several hours) to form a    compound having formula XVI, wherein Q is a halogen (e.g., Cl),    which is then isolated (e.g., quenched with ice, extracted with a    non-polar solvent (e.g., DCM), dried, and concentrated);

-   c) condensing a compound having formula XVI with an indole compound    VIII in the presence of a Lewis acid (e.g., AlCl₃) in a polar    solvent (e.g., 1,2-dichloroethane) e.g., at elevated temperature    (e.g., about 65-70° C.) for a sufficient time (e.g., overnight) to    form a compound having formula XVII, which is then isolated (e.g.,    cooled and quenched with ice, extracted with an organic solvent and    purified by chromatography);

-   d) alkylating or arylating a compound having formula XVII to form a    compound having formula XVIII, which is then isolated (e.g.,    extracted and concentrated to dryness and purified by preparative    LCMS);

-   e) alkylating a compound having formula XVIII with a halogenated    acetic acid alkyl ester (e.g., t-butyl bromoacetate) in a solvent    (e.g. DMF) in the presence of a base (e.g., K₂CO₃) e.g., at elevated    temperature (e.g., about 75-100° C.) for a sufficient time (e.g.,    several hours) to form a compound having formula XIX, which is then    isolated (e.g., extracted and concentrated to dryness); and

-   f) deprotecting a compound having formula XIX e.g., with an organic    acid (e.g., TFA) e.g., at about room temperature to form a compound    having formula XX, which is then isolated (e.g., concentrated to    dryness and purified by preparative LCMS).

In one embodiment, the invention relates to a method of preparing acompound having formula XX, comprising deprotecting a compound havingformula XIX to form a compound having formula XX.

In one embodiment, the invention relates to a method of preparing acompound having formula XXIV, comprising

-   a) condensing a compound having formula VIII with a 1,4-dihalo    phthalazine compound (e.g., 1,4-dichlorophthalazine) in the presence    of a Lewis acid (e.g., AlCl₃) in a polar solvent (e.g.,    1,2-dichloroethane) at elevated temperature (e.g., about 65° C.) for    a sufficient time (e.g., overnight) to form a compound having    formula XXI, wherein Q is halogen (e.g., Cl), which is then isolated    (e.g., cooled and quenched with water, filtered, and dried);

-   b) alkylating a compound having formula XXI with a halogenated    acetic acid ester (e.g., t-butyl bromoacetate) in a solvent (e.g.,    DMF) in the presence of a base (e.g., K₂CO₃) at about room    temperature for several hours to form a compound having formula    XXII;

-   c) hydrolyzing a compound having formula XXII with an organic acid    (e.g., acetic acid) e.g., in the presence of a base (e.g., NaOH) at    elevated temperature (e.g., about 70° C.) for a sufficient time    (e.g., several hours) to form a compound having formula XXIII, which    is then isolated (e.g., cooled, extracted, dried, and concentrated);    and

-   d) alkylating or arylating a compound having formula XXIII (e.g.,    with benzyl bromide) followed by deprotecting to form a compound    having formula XXIV.

In one embodiment, the invention relates to a method of preparing acompound having formula XXIV, comprising alkylating or arylating acompound having formula XXIII followed by deprotecting to form acompound having formula XXIV.

In one embodiment, the invention relates to a method of preparing acompound having formula XXVIII, comprising

-   a) reducing a compound having formula XXV with a reducing agent    (e.g., NaBH₄) in a polar solvent (e.g., methanol) e.g., at reduced    temperature (e.g., about 0° C.) and then about room temperature to    form a compound having formula XXVI, which is then isolated (e.g.,    quenched e.g., with an organic acid (e.g., acetic acid), extracted    e.g., with a non-polar solvent (e.g., DCM), washed, and    concentrated);

-   b) condensing a compound having formula XXVI with an indole compound    VIII e.g., at elevated temperature (e.g., about 180° C.) for a    sufficient time (e.g., about 30 minutes) to form a compound having    formula XXVII, which is then isolated (e.g., cooled and    recrystallized (e.g., from ethanol/water)); and

-   c) alkylating a compound having formula XXVII with a halogenated    acetic acid alkyl ester (e.g., t-butyl bromoacetate) in a solvent    (e.g., DMF) in the presence of a base (e.g., K₂CO₃) at elevated    temperature (e.g., about 80-100° C.) for a sufficient time (e.g.,    several hours), followed by deprotection e.g., with an organic acid    (e.g., TFA), to form a compound having formula XXVIII, which is then    isolated (e.g., extracted to dryness and purified by LCMS).

In one embodiment, the invention relates to a method of preparing acompound having formula XXVIII, comprising condensing a compound havingformula XXVII with a halogenated acetic acid alkyl ester followed bydeprotecting to form a compound having formula XXVIII.

In one embodiment, the invention relates to a method of preparing acompound having formula XXXI, comprising

-   a) methylating a compound having formula XXIX with a methylating    agent (e.g., MeMgBr) in the presence of a Lewis acid (e.g., Me₃Al)    at reduced temperature (e.g., 0° C.) to form a compound having    formula XXX, which may then be isolated (e.g., extracted, dried, and    purified by silica gel chromatography); and

-   b) alkylating or arylating a compound having formula XXX in a    solvent (e.g., DMF) in the presence of a base (e.g., K₂CO₃) at    elevated temperature (e.g., about 80-100° C.) for a sufficient time    (e.g., several hours), followed by deprotection e.g., with an    organic acid (e.g., TFA), to form a compound having formula XXXI,    which is then isolated (e.g., extracted to dryness and purified by    LCMS).

In one embodiment, the invention relates to a method of preparing acompound having formula XXXI, comprising alkylating or arylating acompound having formula XXX to form a compound having formula XXXI.

In one embodiment, the invention relates to a method of preparing acompound having formula XXXVIII, comprising

-   a) alkylating a compound having formula XXXII with a halogenated    acetic acid alkyl ester (e.g., t-butyl bromoacetate) in a solvent    (e.g., DMF) in the presence of a base (e.g., K₂CO₃) at elevated    temperature (e.g., about 80-100° C.) for a sufficient time (e.g.,    several hours) to form a compound having formula XXXIII, which may    then be isolated (e.g., extracted, dried, and purified by silica gel    chromatography);

-   b) condensing a compound having formula XXXIII with    2-phenylethenesulfonic acid amide in a solvent (e.g., toluene) at    elevated temperature (e.g., about 80-100° C.) for a sufficient time    (e.g., several hours) to form a compound having formula XXXIV, which    may then be isolated (e.g., extracted, dried, and purified by silica    gel chromatography);

-   c) alkylating a compound having formula XXXIV with an alkylating    agent (e.g., CH₂CHMgBr) in the presence of a Lewis acid (e.g.,    Me₃Al) at room temperature for a sufficient time (e.g., 10-30    minutes) to form a compound having formula XXXV, which may then be    isolated (e.g., extracted, dried, and purified by silica gel    chromatography);

-   d) cyclizing a compound having formula XXXV in the presence of a    catalyst (e.g., 5% Grubb's catalyst) in a solvent (e.g., DCM) at    elevated temperature for a sufficient time (e.g., several hours) to    form a compound having formula XXXVI, which is then isolated (e.g.,    by silica gel chromatography);

-   e) alkylating or arylating a compound having formula XXXVI in a    solvent (e.g., DMF) in the presence of a base (e.g., K₂CO₃) at    elevated temperature (e.g., about 80-100° C.) for a sufficient time    (e.g., several hours) to form a compound having formula XXXVII,    which may then be isolated (e.g., extracted, dried, and purified by    silica gel chromatography); and

-   f) reducing a compound having formula XXXVII with a reducing agent    (e.g., NaBH₄) in a solvent (e.g., isopropanol) at elevated    temperature, followed by deprotection with a base (e.g., NaOH) in a    solvent (e.g., ethanol) at elevated temperature (e.g., about 80-100°    C.) for a sufficient time (e.g., several hours) to form a compound    having formula XXXVIII, which may then be isolated (e.g., extracted    to dryness and purified by LCMS).

In one embodiment, the invention relates to a method of preparing acompound having formula XXXVIII, comprising reducing a compound havingformula XXXVII followed by deprotecting to form a compound havingformula XXXVIII.

In one embodiment, the invention relates to a method of preparing acompound having formula XLII, comprising

-   a) acylating an indole compound having formula VIII with a compound    having formula XXXIX in the presence of a Lewis acid (e.g., AlCl₃)    (e.g., about 60-80° C.) for a sufficient time (e.g., several hours)    to form a compound having formula XL;

-   b) cyclizing a compound having formula XL with an alkylhydrazide    (e.g., R₁NHNH₂) in a solvent (e.g., toluene) at elevated temperature    for a sufficient time (e.g., several hours) to form a compound    having formula XLI; and

-   c) alkylating a compound having formula XLI with a halogenated    acetic acid alkyl ester (e.g., t-butyl bromoacetate) in a solvent    (e.g., DMF) in the presence of a base (e.g., K₂CO₃) at elevated    temperature (e.g., about 80-100° C.) for a sufficient time (e.g.,    several hours), followed by deprotection e.g., with an organic acid    (e.g., TFA), to form a compound having formula XLII, which may then    be isolated (e.g., extracted to dryness and purified by LCMS).

In one embodiment, the invention relates to a method of preparing acompound having formula XLII, comprising condensing a compound havingformula XLI with a halogenated acetic acid alkyl ester followed bydeprotecting to form a compound having formula XLII.

An important aspect of the present invention is that compounds ofFormula I inhibit the binding of PGD₂ and its metabolites, as well asany other endogenous ligands, to the CRTH2 receptor. Therefore, it iscontemplated that these compounds inhibit the effects of PGD₂ or itsmetabolites or other ligands on cells containing CRTH2 receptors. Theinhibitors of the present invention can be used to block the effect ofendogenous ligands of the CRTH2 receptor in any disorder that can betreated, ameliorated, or prevented by blocking the CRTH2 receptor. Thus,the present invention provides compositions and methods for targetinganimals characterized as having elevated levels of PGD₂ or otherendogenous ligands of the CRTH2 receptor. The present invention alsocontemplates methods of treating animals having normal levels of PGD₂ orother endogenous ligands of the CRTH2 receptor that would benefit fromdecreasing the effects of these molecules to sub-normal levels.

In some embodiments, the compositions and methods of the presentinvention are used to treat diseased cells, tissues, organs, orpathological conditions and/or disease states in an animal (e.g., amammalian subject including, but not limited to, humans and veterinaryanimals). In this regard, various disorders, diseases and pathologiesare amenable to treatment or prophylaxis using the present methods andcompositions. A non-limiting list of these diseases and conditionsincludes, but is not limited to, disorders of the respiratory tract,including asthma, chronic obstructive pulmonary disease, bronchitis,rhinitis, nasal polyposis, sarcoidosis, farmer's lung, fibroid lung,idiopathic interstitial pneumonia, cystic fibrosis, and cough; disordersof the bones and joints, including arthritis, ankylosing spondylitis,Reiter's disease, Behcet's disease, Sjorgren's syndrome, and systemicsclerosis; disorders of the skin and eyes, including psoriasis,dermatitis, Lichen planus, pemphigus, epidermolysis bullosa, urticaria,angiodermas, vasculitides, erythemas, cutaneous eosinophilias, chronicskin ulcers, uveitis, corneal ulcers, and conjunctivitis; disorders ofthe gastrointestinal tract, including celiac disease, proctitis,gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis,irritable bowel disease, and food-related allergies; disorders of thecentral and peripheral nervous system, including Alzheimer's disease,amyotrophic lateral sclerosis, Creutzfeldt-Jacob's disease, AIDSdementia complex, Huntington's disease, Guillain-Barre syndrome,multiple sclerosis, encephalomyelitis, myasthenia gravis, tropicalspastic paraparesis, CNS trauma, migraine, and stroke; disorders ofother tissues and systemic disorders, including atherosclerosis, AIDS,lupus erythematosus, Hashimoto's thyroiditis, type I diabetes, nephroticsyndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy,thrombocytopenia purpura, post-operative adhesions, sepsis,ischemic/reperfusion injury, hepatitis, glomerulonephritis, and chronicrenal failure; and acute and chronic allograft rejection

Some embodiments of the present invention provide methods foradministering an effective amount of a compound of Formula I and atleast one additional therapeutic agent. The additional therapeutic agentmay be any therapeutic agent that has been used, is currently used, oris known to be useful for treating, ameliorating, or preventing adisorder encompassed by the present invention. For example, theadditional therapeutic agent may be another compound that inhibitsbinding to the CRTH2 receptor (e.g., indomethacin). In anotherembodiment, the additional therapeutic drug is one that has acomplementary effect to the compounds of the present invention. For amore detailed description of therapeutic agents, those skilled in theart are referred to instructive manuals including, but not limited to,the Physician's Desk Reference and to Goodman and Gilman's“Pharmaceutical Basis of Therapeutics” ninth edition, Eds. Hardman etal., 1996. The combination of a compound of the invention and one ormore therapeutic agents can have additive potency or an additivetherapeutic effect. The invention also encompasses synergisticcombinations where the therapeutic efficacy is greater than additive.Preferably, such combinations also reduce or avoid unwanted or adverseeffects. In certain embodiments, the combination therapies encompassedby the invention provide an improved overall therapy relative toadministration of a compound of Formula I or any therapeutic agentalone. In certain embodiments, doses of existing or experimentaltherapeutic agents can be reduced or administered less frequently whichincreases patient compliance, thereby improving therapy and reducingunwanted or adverse effects.

Examples of useful therapeutic agents include, but are not limited to,agents used to treat asthma and rhinitis (steroids (e.g., budesomide),β2-receptor agonists (e.g., albuterol), leukotriene receptor antagonists(e.g., montelukast)), agents used to treat autoimmune disease(glucocorticoids, cyclosporine, tacrolimus, mycophenolate mofetil),agents used to treat nervous system disorders (anticholinesterases,dopamine, levodopa, serotonin receptor agonists (e.g., sumatriptan),amantadine, donepezil, riluzole), agents used to treatischemia/reperfusion injury (nitroglycerin, nifedipine), and agents usedto treat gastrointestinal disorders (neostigmine, metoclopramide,sulfasalazine).

In some embodiments of the present invention, a compound of Formula Iand one or more therapeutic agents are administered to an animal atdifferent periodicities, at different durations, at differentconcentrations, by different administration routes, etc. In someembodiments, the compound is administered prior to the therapeuticagent, e.g., 0.5, 1, 2 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6days, 1, 2, 3, or 4 weeks prior to the administration of the therapeuticagent. In some embodiments, the compound is administered after thetherapeutic agent, e.g., 0.5, 1, 2 3, 4, 5, 10, 12, or 18 hours, 1, 2,3, 4, 5, or 6 days, 1, 2, 3, or 4 weeks after the administration of thetherapeutic agent. In some embodiments, the compound and the therapeuticagent are administered concurrently but on different schedules, e.g.,the compound is administered daily while the therapeutic agent isadministered once a week, once every two weeks, once every three weeks,or once every four weeks. In other embodiments, the compound isadministered once a week while the therapeutic agent is administereddaily, once a week, once every two weeks, once every three weeks, oronce every four weeks.

Compositions within the scope of this invention include all compositionswherein the compounds of the present invention are contained in anamount which is effective to achieve its intended purpose. Whileindividual needs vary, determination of optimal ranges of effectiveamounts of each component is within the skill of the art. Typically, thecompounds may be administered to animals, e.g. humans, orally at a doseof 0.0025 to 50 mg/kg, or an equivalent amount of the pharmaceuticallyacceptable salt thereof, per day of the body weight of the animal beingtreated for disorders responsive to inhibition of the CRTH2 receptor.Preferably, about 0.01 to about 10 mg/kg is orally administered totreat, ameliorate, or prevent such disorders. For intramuscularinjection, the dose is generally about one-half of the oral dose. Forexample, a suitable intramuscular dose would be about 0.0025 to about 25mg/kg, and most preferably, from about 0.01 to about 5 mg/kg.

The unit oral dose may comprise from about 0.01 to about 50 mg,preferably about 0.1 to about 10 mg of the compound. The unit dose maybe administered one or more times daily as one or more tablets orcapsules each containing from about 0.1 to about 10 mg, convenientlyabout 0.25 to 50 mg of the compound.

In a topical formulation, the compound may be present at a concentrationof about 0.01 to 100 mg per gram of carrier. In a preferred embodiment,the compound is present at a concentration of about 0.07-1.0 mg/ml, morepreferably, about 0.1-0.5 mg/ml, most preferably, about 0.4 mg/ml.

In addition to administering the compound as a raw chemical, thecompounds of the invention may be administered as part of apharmaceutical preparation containing suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of the compounds into preparations which can beused pharmaceutically. Preferably, the preparations, particularly thosepreparations which can be administered orally or topically and which canbe used for the preferred type of administration, such as tablets,dragees, slow release lozenges and capsules, mouth rinses and mouthwashes, gels, liquid suspensions, hair rinses, hair gels, shampoos andalso preparations which can be administered rectally, such assuppositories, as well as suitable solutions for administration byinjection, topically or orally, contain from about 0.01 to 99 percent,preferably from about 0.25 to 75 percent of active compound(s), togetherwith the excipient.

The pharmaceutical compositions of the invention may be administered toany animal which may experience the beneficial effects of the compoundsof the invention. Foremost among such animals are mammals, e.g., humans,although the invention is not intended to be so limited. Other animalsinclude veterinary animals (cows, sheep, pigs, horses, dogs, cats andthe like).

The compounds and pharmaceutical compositions thereof may beadministered by any means that achieve their intended purpose. Forexample, administration may be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, buccal, intrathecal,intracranial, intranasal, or topical routes. Alternatively, orconcurrently, administration may be by the oral route. The dosageadministered will be dependent upon the age, health, and weight of therecipient, kind of concurrent treatment, if any, frequency of treatment,and the nature of the effect desired.

The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample lactose or sucrose, mannitol or sorbitol, cellulose preparationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders such as starch paste, using, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired,disintegrating agents may be added such as the above-mentioned starchesand also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar,or alginic acid or a salt thereof, such as sodium alginate. Auxiliariesare, above all, flow-regulating agents and lubricants, for example,silica, talc, stearic acid or salts thereof, such as magnesium stearateor calcium stearate, and/or polyethylene glycol. Dragee cores areprovided with suitable coatings which, if desired, are resistant togastric juices. For this purpose, concentrated saccharide solutions maybe used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquersolutions and suitable organic solvents or solvent mixtures. In order toproduce coatings resistant to gastric juices, solutions of suitablecellulose preparations such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain the active compounds in the form of granules whichmay be mixed with fillers such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds are preferablydissolved or suspended in suitable liquids, such as fatty oils, orliquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations which can be used rectally include,for example, suppositories, which consist of a combination of one ormore of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatin rectal capsules which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension include, for example, sodium carboxymethylcellulose, sorbitol, and/or dextran. Optionally, the suspension may alsocontain stabilizers.

The topical compositions of this invention are formulated preferably asoils, creams, lotions, ointments and the like by choice of appropriatecarriers. Suitable carriers include vegetable or mineral oils, whitepetrolatum (white soft paraffin), branched chain fats or oils, animalfats and high molecular weight alcohol (greater than C₁₂). The preferredcarriers are those in which the active ingredient is soluble.Emulsifiers, stabilizers, humectants and antioxidants may also beincluded as well as agents imparting color or fragrance, if desired.Additionally, transdermal penetration enhancers can be employed in thesetopical formulations. Examples of such enhancers can be found in U.S.Pat. Nos. 3,989,816 and 4,444,762.

Creams are preferably formulated from a mixture of mineral oil,self-emulsifying beeswax and water in which mixture the activeingredient, dissolved in a small amount of an oil such as almond oil, isadmixed. A typical example of such a cream is one which includes about40 parts water, about 20 parts beeswax, about 40 parts mineral oil andabout 1 part almond oil.

Ointments may be formulated by mixing a solution of the activeingredient in a vegetable oil such as almond oil with warm soft paraffinand allowing the mixture to cool. A typical example of such an ointmentis one which includes about 30% almond oil and about 70% white softparaffin by weight.

Lotions may be conveniently prepared by dissolving the activeingredient, in a suitable high molecular weight alcohol such aspropylene glycol or polyethylene glycol.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in clinical therapy and which are obvious to those skilledin the art are within the spirit and scope of the invention.

General Analytical Conditions:

HPLC analysis and purification was performed using a Waters 2525 binarygradient pump, Waters 2767 sample manager, Waters 2487 UV detector (220and 254 nM), and Waters Micromass ZQ electrospray mass spec detector.The Micromass ZQ was set for both positive and negative ionization (conevoltage=25 and 50, respectively).

Analytical HPLC analysis was performed as follows:

-   Waters XTerra MS C18 50×4.6 mm 3.5 μm column-   Mobile Phase: 10 mM Ammonium Acetate buffer at pH 5.75 and    Acetonitrile-   Acetonitrile: 10 to 75% at 3.5 minutes, 75 to 99% at 3.9 minutes,    99% hold to 4.2 minutes, 99 to 10% at 4.5 minutes, re-equilibrate.

Preparative HPLC was performed as follows:

-   Waters XTerra Prep MS C18 50×19 mm 5 μm column-   Mobile Phase: 10 mM Ammonium Acetate buffer at pH 5.75 and    Acetonitrile-   Acetonitrile: 10 to 99% at 8 minutes, 99% hold to 9 minutes, 99 to    10% at 9.5 minutes, re-equilibrate.

NMR analysis was performed using a Bruker BioSpin UltraSheild NMR (300MHz).

EXAMPLE 1[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid a.) 3-Chloro-benzo[d]isothiazole 1,1-dioxide (Wade et al., U.S.Pat. No. 4,140,693) (Scheme 1)

Saccharin (10 g) was treated sequentially with dioxane (40 mL), thionylchloride (15 mL) and DMF (0.4 mL). The resulting suspension was heatedto reflux for 24 hours. The reaction mixture was concentrated to drynessand recrystalized from 60 mL toluene to give 5.7 g of the sub-titlecompound as a white solid.

b.) 3-(1H-Indol-3-yl)-benzo[d]isothiazole 1,1-dioxide

Indole (117 mg, 1 mmol) and 3-chloro-benzo[d]isothiazole 1,1-dioxide(201 mg, 1 mmol) were treated 5 mL of 1,2-dichloroethane followed byAlCl₃ (160 mg, 1.2 mmol). The reaction mixture was heated to 65° C.overnight, then cooled and quenched with water (1 mL). The resultingsolid was filtered, washed with water, and dried to give 0.3 grams ofthe sub-title compound. MS: ESI (negative): 281 (M−H).

c.) [3-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester

A solution of the product from example 1, step b (300 mg) was dissolvedin DMF and treated with K₂CO₃ (166 mg, 1.2 mmol) followed by t-butylbromoacetate (150 μL, 1 mmol). The reaction was heated to 80° C. for 1h. Additional K₂CO₃ and t-butyl bromoacetate were added (1 mmol each)and the reaction was heated to 100° C. for 2 h. The reaction was cooledand partitioned between EtOAc and water. The organic layer was washedwith water 3 times then dried over MgSO₄ and concentrated to give thesub-title compound as a yellow solid. MS: ESI (positive): 397 (M+H).

d.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester

A solution of the product from example 1, step c (100 mg, 0.25 mmol) wasdissolved in 4 mL MeOH. NaBH₄ (30 mg, 0.75 mmol) was added and thereaction was stirred at rt for ½ h. Additional NaBH₄ was added as neededin order to push the reaction to completion. The reaction was carefullyquenched with HOAc until the evolution of hydrogen ceased. The resultingsolution was partitioned between dichloromethane (DCM) and H₂O. Theorganic layer was dried over MgSO₄ and concentrated to an orange oilthat was used without further purification. MS: ESI (negative): 397(M−H).

e.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid

The product of example 1, step d (32 mg, 0.08 mmol) was treated withtrifluoroacetic acid (TFA) (neat) or 70% TFA in DCM. After stirring 2-24h, the reaction was concentrated to dryness and purified by preparativeLCMS to give the title compound. ¹H NMR (DMSO-d₆) δ 7.90-7.86 (m, 1H),7.66-7.57 (m, 2H), 7.38 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.25-7.20 (m,2H), 7.06 (t, J=7.2 Hz, 1H), 6.87 (t, J=7.2 Hz, 1H), 6.07 (s, 1H), 4.62(s, 2H); MS: ESI (negative): 341 (M−H).

EXAMPLE 2[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-methyl-indol-1-yl]-aceticacid a.) 3-(5-Methyl-1H-indol-3-yl)-benzo[d]isothiazole 1,1-dioxide(Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 5-methyl indole.

b.)[3-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a).

c.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-methyl-indol-1-yl]-aceticacid

The title-compound was prepared as described for example 1, step e)using the product from step c). MS: ESI (negative): 355 (M−H).

EXAMPLE 3[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid a.) 3-(2-Methyl-1H-indol-3-yl)-benzo[d]isothiazole 1,1-dioxide(Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 2-methyl indole. The product did not crystallize upon quenching,and was instead purified by partitioning between DCM and water.

b.)[3-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a). This compound was purified bychromatography (EtOAc/Hex) prior to use in subsequent steps.

c.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid

The title-compound was prepared as described for example 1, step e)using the product from step c). MS: ESI (negative): 355 (M−H).

EXAMPLE 4[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-methoxy-indol-1-yl]-aceticacid a.) 3-(5-Methoxy-1H-indol-3-yl)-benzo[d]isothiazole 1,1-dioxide(Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 5-methoxy indole.

b.)[3-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-methoxy-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a).

c.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-methoxy-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-methoxy-indol-1-yl]-aceticacid

The title-compound was prepared as described for example 1, step e)using the product from step c). MS: ESI (negative): 371 (M−H).

EXAMPLE 5 [5-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid a.) 3-(5-Chloro-1H-indol-3-yl)-benzo[d]isothiazole 1,1-dioxide(Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 5-chloro indole.

b.)[5-Chloro-3-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a).

c.)[5-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[5-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid

The product from step c) (100 mg) was dissolved in 3 mL EtOH and treatedwith 0.5 mL of 1 M NaOH. The reaction was heated to 50° C. for 2 h. Uponcooling, the reaction was washed with DCM, acidified with 1 M HCl, andextracted into DCM. The organic layer was washed twice with water, driedover MgSO₄, and concentrated to give the title compound as a solid. MS:ESI (negative): 375, 377 (M−H).

EXAMPLE 6[5-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid a.) 3-(5-Chloro-2-methyl-1H-indol-3-yl)-benzo[d]isothiazole1,1-dioxide (Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 5-chloro-2-methyl indole.

b.)[5-Chloro-3-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a).

c.)[5-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[5-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid

The title compound was prepared as described for example 5, step d)using the product from step c). ¹H NMR (DMSO-d₆) 12.95 (bs, 1H), 7.93(s, 1H), 7.93-7.90 (m, 1H), 7.64-7.57 (m, 2H), 7.40 (d, J=9.0 Hz, 1H),7.07-7.04 (m, 1H), 7.00 (dd, J=2.1, 8.7 Hz, 1H), 6.92 (s, 1H), 6.16 (s,1H), 5.00 (s, 2H), 2.39 (s, 3H); MS: ESI (negative): 389, 391 (M−H).

EXAMPLE 7[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2,5-dimethyl-indol-1-yl]-aceticacid a.) 3-(2,5-Dimethyl-1H-indol-3-yl)-benzo[d]isothiazole 1,1-dioxide(Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 2,5-dimethyl indole.

b.)[3-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2,5-dimethyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a).

c.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2,5-dimethyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2,5-dimethyl-indol-1-yl]-aceticacid

The title compound was prepared as described for example 5, step d)using the product from step c). MS: ESI (negative): 369 (M−H).

EXAMPLE 8[5-Bromo-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid a.) 3-(5-Bromo-1H-indol-3-yl)-benzo[d]isothiazole 1,1-dioxide(Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 5-bromo indole.

b.)[5-Bromo-3-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a).

c.)[5-Bromo-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[5-Bromo-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid

The title compound was prepared as described for example 5, step d)using the product from step c). MS: ESI (negative): 419, 421 (M−H).

EXAMPLE 9[5-Cyano-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid a.)3-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-1H-indole-5-carbonitrile(Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 5-cyano indole.

b.)[5-Cyano-3-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a).

c.)[5-Cyano-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[5-Cyano-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid

The title compound was prepared as described for example 5, step d)using the product from step c). MS: ESI (negative): 366 (M−H).

EXAMPLE 10[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid a.) 3-(5-Fluoro-2-methyl-1H-indol-3-yl)-benzo[d]isothiazole1,1-dioxide (Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 5-fluoro-2-methyl indole.

b.)[3-(1,1-Dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a).

c.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[3-(1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid

The title compound was prepared as described for example 5, step d)using the product from step c). MS: ESI (negative): 373 (M−H).

EXAMPLE 11[4-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid a.) 3-(4-Chloro-1H-indol-3-yl)-benzo[d]isothiazole 1,1-dioxide(Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 4-chloro indole.

b.)[4-Chloro-3-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a).

c.)[4-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[4-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid

The title compound was prepared as described for example 5, step d)using the product from step c). ¹H NMR (DMSO-d₆) δ 13.00 (bs, 1H), 8.34(bd, J=4.2 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.65 (t, J=7.0 Hz, 1H), 7.58(t, J=7.2 Hz, 1H), 7.43-7.55 (m, 2H), 7.19-7.11 (m, 3H), 6.52 (s, 1H),5.00 (s, 2H); MS: ESI (negative): 375, 377 (M−H).

EXAMPLE 12[6-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid a.) 3-(6-Chloro-1H-indol-3-yl)-benzo[d]isothiazole 1,1-dioxide(Scheme 1)

The sub-title compound was prepared as described for example 1, step b)using 6-chloro indole.

b.)[6-Chloro-3-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step a).

c.)[6-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step b).

d.)[6-Chloro-3-(1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid

The title compound was prepared as described for example 5, step d)using the product from step c). ¹H NMR (DMSO-d₆) δ 13.01 (bs, 1H), 8.46(d, J=3.6 Hz, 1H), 7.90-7.87 (m, 1H), 7.63-7.58 (m, 2H), 7.64 (d, J=1.8Hz, 1H), 7.45 (s, 1H), 7.26 (d, 1H, J=8.7 Hz), 7.23-7.29 (m, 1H), 6.97(dt, J=1.5, 8.4 Hz, 1H), 6.09 (d, J=3.0 Hz, 1H), 5.04 (s, 2H); MS: ESI(negative): 375, 377 (M−H).

EXAMPLE 13[3-(6-Fluoro-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid a.) 5-Fluorosaccharin (Scheme 1)

5-Fluoro-2-methyl-benzenesulfonyl chloride (1 g, 4.7 mmol) in 5 mL THFwas added dropwise to a solution of ammonium hydroxide (1.6 mL, 15 mmol)in 10 mL THF. After stirring 1 h, the reaction was concentrated todryness. The resulting solid was dissolved in 10 mL of 1 M NaOH andtreated with KMnO₄ (2.4 g). The solution was heated to 50° C. overnight.The resulting solution was filtered through celite and acidified to pH˜1 with 10% HCl. After standing for several minutes, a precipitateformed. The precipitate was filtered, washed with water, and dried togive 0.29 grams of the sub-title compound as a white solid.

b.) 3-Chloro-6-fluoro-benzo[d]isothiazole 1,1-dioxide

The product from step a) (0.29 g) was treated with 4 mL dioxane, 1.5 mLthionyl chloride, and 40 μL DMF. The resulting solution was heatedovernight at reflux and subsequently concentrated to dryness. The crudeintermediate was used without further purification.

c.) 6-Fluoro-3-(2-methyl-1H-indol-3-yl)-benzo[d]isothiazole 1,1-dioxide

The sub-title compound was prepared as described for example 1, step b)using 2-methyl indole and the product from step b). The product did notcrystallize upon quenching, and was instead purified by partitioningbetween DCM and water.

d.)[3-(6-Fluoro-1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step c)using the product from step c).

e.)[3-(6-Fluoro-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared as described for example 1, step d)using the product from step d).

f.)[3-(6-Fluoro-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid

The title compound was prepared as described for example 1, step e)using the product from step e). MS: ESI (negative): 373 (M−H).

EXAMPLE 14[3-(2-Methyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid

(Scheme 1)

The intermediate from example 1, step d (33 mg, 0.08 mmol) was dissolvedin DMF (1 mL) and treated with K₂CO₃ (28 mg, 0.2 mmol) followed bymethyl iodide. The reaction was heated to 70°-80° C. for 1 h. Thereaction mixture was cooled and partitioned between EtOAc and water. Theorganic layer was washed several times with water then concentrated todryness. The crude residue was then treated with TFA (2 mL) for 2 h. Thereaction was concentrated and purified by preparative LCMS to give thetitle compound. ¹H NMR (DMSO-d6) δ 8.22-8.20 (m, 1H), 7.88-7.85 (m, 2H),7.81 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.40-7.35 (m, 1H), 7.28 (t, J=7.5Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 5.94 (s, 1H),4.80 (s, 2H), 2.88 (s, 3H); MS: ESI (negative): 355 (M−H).

EXAMPLE 15[3-(3-Benzyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-indol-1-yl]-acetic acida.) 1-Chloro-4-(1H-indol-3-yl)-phthalazine (Scheme 3)

The sub-title compound was prepared in one step as described by Pal etal., J. Org. Chem. 68:6806 (2003).

b.) [3-(4-Chloro-phthalazin-1-yl)-indol-1-yl]-acetic acid tert-butylester

The product of step a) (280 mg, 1 mmol) was dissolved in 10 mL DMF andtreated with 1.6 mmol t-butyl bromoacetate followed by K₂CO₃ (1.4 mmol).The reaction was stirred overnight at rt then partitioned between EtOAcand water. The organic layer was washed 3 times with water, dried overMgSO₄ and concentrated to give the sub-title compound as a while solid.MS: ESI (positive): 394 (M+H).

c.) [3-(4-Oxo-3,4-dihydro-phthalazin-1-yl)-indol-1-yl]-acetic acid

The product of step b) (50 mg, 0.13 mmol) was dissolved in 4 mL THF.NaOH (0.52 mL of 1 M aq) was added and the reaction was heated to 60° C.for 3 days. The reaction was cooled, acidified with 1 M HCl, andextracted into DCM. Concentration gave the sub-title product as a yellowoil. MS: ESI (negative): 318 (M−H).

d.) [3-(3-Benzyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-indol-1-yl]-aceticacid

The product of step c) was dissolved in DMF (4 mL) and treated withK₂CO₃ (55 mg, 0.4 mmol) and benzyl bromide (0.25 mmol). The reaction washeated to 70° C. for 12 h. Additional K₂CO₃ (0.2 mmol) and benzylbromide (0.25 mmol) was added and heating was continued for 3 h. Thereaction was cooled and partitioned between EtOAc and water. The organiclayer was washed 3 times with water and concentrated. The residue wasdissolved in EtOH (2 mL) and treated with NaOH (0.5 mL, 1 M). Afterheating to 70° C. for 1 h, the reaction was cooled, acidified with HCl,and extracted into DCM. The organic layer was concentrated, dissolved inDMF, and purified by preparative LCMS. ¹H NMR (DMSO-d₆) δ 8.41 (d, J=6.9Hz, 1H), 8.16 (d, J=7.2 Hz, 1H), 7.98-7.89 (m, 2H), 7.87 (s, 1H), 7.61(d, J=8.1 Hz, 1H), 7.44-7.27 (m, 6H), 7.17 (t, J=7.3 Hz, 1H), 7.03 (t,J=7.5 Hz, 1H), 5.43 (s, 2H), 4.80 (s, 2H); MS: ESI (negative): 408(M−H).

EXAMPLE 16[3-(3-Benzyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid a.) 1-Chloro-4-(5-chloro-2-methyl-1H-indol-3-yl)-phthalazine(Scheme 3)

5-Chloro-2-methylindole (0.74 g, 2.26 mmol) and 1,4-dichloro-phthalazine(0.45 g, 2.26 mmol) were treated with 30 mL of 1,2-dichloroethane and3.2 mmol of AlCl₃ (427 mg). The resulting suspension was heated to 65°C. overnight. The reaction was cooled and quenched with 3 mL water. Theresultant precipitate was filtered and dried under vacuum to give 0.65 gof the sub-title compound. MS: ESI (negative): 326, 328 (M−H).

b.) [5-Chloro-3-(4-chloro-phthalazin-1-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared from the product of step a) usingthe procedure described in example 15, step b). MS: ESI (positive): 442,444 (M+H).

c.)[5-Chloro-2-methyl-3-(4-oxo-3,4-dihydro-phthalazin-1-yl)-indol-1-yl]-aceticacid tert-butyl ester

The product of step b) (300 mg) was treated with 10 mL HOAc and 2 mL of1 M NaOH. The suspension was heated to 70° C. for 4 h. The reaction wascooled and partitioned between EtOAc and water. The organic layer wasdried over MgSO₄ and concentrated to give 300 mg of the sub-titlecompound as a yellow oil. MS: ESI (negative): 422, 424 (M−H).

d.)[3-(3-Benzyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid

The sub-title compound was prepared from the product of step c) andbenzyl bromide using the procedure described in example 14. ¹H NMR(DMSO-d₆) δ 13.20 (bs, 1H), 8.37-8.34 (m, 1H), 7.88-7.80 (m, 2H), 7.52(d, J=9.3 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.36-7.09 (m, 7H), 5.39 (d,J=15 Hz, 1H), 5.35 (d, J=15 Hz, 1H), 5.08 (s, 2H), 2.18 (s, 3H); MS: ESI(negative): 456, 458 (M−H).

EXAMPLE 17[3-(2-Benzyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-indol-1-yl]-aceticacid a.) 1,1-Dioxo-2,3-dihydro-1H-1λ⁶-benzo[e][1,2,3]thiadiazin-4-one(Scheme 2)

2-Chlorosulfonyl-benzoic acid methyl ester (7.04 g, 30 mmol) was addedto hydrazine hydrate (66 mmol) stirring rapidly in 300 mL ether. Thereaction was stirred overnight in an open flask and allowed to slowlyconcentrate. The remaining solvent was concentrated and the residue wastreated with HOAc (3 mL) and DCM. The solution was washed with water,dried over MgSO₄, and concentrated to give 3 g of a white solid.

b.) 4-Chloro-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide

The product of step a) (300 mg) was treated with 5 mL POCl₃ and 2 dropsDMF and heated to 100° C. overnight. The reaction was quenched over iceand immediately extracted into DCM. After drying over MgSO₄ andconcentrating, the sub-title compound was isolated as an orange oil (240mg). MS: ESI (negative): 215, 217 (M−H).

c.) 4-(1H-Indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide

The product of step b) (0.55 g, 2.5 mmol) was heated with indole (0.29g, 2.5 mmol) and AlCl₃ (0.47 g, 3.5 mmol) in 25 mL 1,2-dichloroethane to70° C. for 2 days. The reaction was quenched over ice and partitionedbetween water and DCM/EtOH. The organic layer concentrated and thesub-title compound was purified by chromatography (EtOAc/Hex) to give435 mg of a foam. MS: ESI (negative): 296 (M−H).

d.)[3-(2-Benzyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-indol-1-yl]-aceticacid

The product of step c) (93 mg, 0.3 mmol) was dissolved in 3 mL DMF andtreated with K₂CO₃ (50 mg, 0.36 mmol) and benzyl bromide (57 mg, 0.33mmol). After stirring at 75° C. overnight, t-butyl bromoacetate (0.36mmol, 70 mg) and was added along with an additional quantity of K₂CO₃(0.39 mmol, 54 mg). The reaction was heated for an additional 2 hours.The crude reaction was partitioned between EtOAc and water. The organiclayer was concentrated to dryness and treated with TFA (3 mL). After 1h, the reaction was concentrated and purified by preparative LCMS togive the title compound. ¹H NMR (DMSO-d₆) δ 8.15 (d, 1H, J=3.6 Hz),8.07-7.94 (m, 3H), 7.92 (s, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.51-7.31 (m,6H), 7.22 (t, J=7.2 Hz, 1H), 7.04 (t, J=7.8 Hz, 1H), 5.12 (s, 2H), 5.07(s, 2H); MS: ESI (negative): 444 (M−H).

EXAMPLE 18[3-(2-Methyl-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl)-indol-1-yl]-aceticacid

(Scheme 2)

The product of Example 17, step c) was alkylated with methyl iodide andt-butyl bromoacetate following the procedure described in example 17,step d). ¹H NMR (DMSO-d₆) δ 8.11-7.90 (m, 5H), 7.85 (s, 1H), 7.44 (d,J=8.1 Hz, 1H), 7.22 (dt, J=0.9, 7.5 Hz, 1H), 7.15 (dt, J=1.2, 7.5 Hz,1H), 4.72 (s, 2H), 3.51 (s, 3H); MS: ESI (negative): 368 (M−H).

EXAMPLE 19[3-(1,1-Dioxo-2-phenethyl-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl)-2-methyl-indol-1-yl]-aceticacid a.) 4-(2-Methyl-1H-indol-3-yl)-2H-benzo[e] [1,2,3]thiadiazine1,1-dioxide (Scheme 2)

The product of Example 17, step b) (1.5 g, 7 mmol) was heated with2-methylindole (0.92 g, 7 mmol) and AlCl₃ (1.12 g, 8.4 mmol) in 70 mL1,2-dichloroethane to 70° C. for 3 days. The reaction was quenched withwater (2 mL) and cooled. The resulting precipitate was filtered andsubsequently purified by chromatography (EtOAc/Hex) to give 200 mg ofthe sub-title compound. MS: ESI (negative): 296 (M−H).

b.)[3-(1,1-Dioxo-2-phenethyl-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl)-2-methyl-indol-1-yl]-aceticacid

The product of step a) was alkylated with 2-bromoethylbenzene andt-butyl bromoacetate following the procedure described in example 17,step d). ¹H NMR (DMSO-d₆) δ 8.05 (d, J=6.9 Hz, 1H), 7.89 (t, J=7.6 Hz,1H), 7.80 (t, J=7.8 Hz, 1H), 7.45-7.40 (m, 2H), 7.27-7.16 (m, 6H), 4.67(s, 2H), 4.13 (t, J=7.2 Hz, 2H), 3.14 (t, J=7.2 Hz, 2H), 2.26 (s, 3H);MS: ESI (negative): 472 (M−H).

EXAMPLE 20[3-(2-Methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-indol-1-yl]-acetic acida.) 3-Hydroxy-2-methyl-2,3-dihydro-isoindol-1-one (Scheme 4)

NaBH₄ (566 mg, 14.91 mmol) was added to a stirring solution of2-methyl-isoindole-1,3-dione (2.0 g, 12.42 mmol) in methanol (20 mL) at0° C. Stirring at 0° C. was maintained for 1 hour, then the reaction waswarmed to room temperature. Additional NaBH₄ (566 mg, 14.91 mmol) wasadded in order to push the reaction to completion. The reaction was thenquenched with acetic acid (5 mL) and partitioned between water anddichloromethane. The organic layer was washed several times with waterand concentrated under vacuum to give 659 mg of the sub-title compoundas a white solid. MS: ESI (positive): 164 (M+H).

b.) 3-(1H-Indol-3-yl)-2-methyl-2,3-dihydro-isoindol-1-one- (Rees et al.,J. Chem. Soc. 687 (1965))

The product from example 20, step a) (650 mg, 3.98 mmol) and indole (780mg, 6.67 mmol) were heated (neat) to 180° C. for 30 minutes. Thereaction was cooled to rt and the product was recrystallized fromethanol/water to give 452 mg of the sub-title compound as a tan solid.

c.) [3-(2-Methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-indol-1-yl]-aceticacid

The product from example 20, step b) (450 mg, 1.72 mmol) was dissolvedin DMF and treated with K₂CO₃ (284 mg, 2.06 mmol) followed by t-butylbromoacetate (255 μL, 1.72 mmol). The reaction was heated to 100° C. for5 h. The reaction was cooled, diluted with EtOAc, washed 3 times withwater, and concentrated. The crude product was treated with TFA (neat)at room temperature for 45 minutes. The reaction was then concentratedto dryness and purified by preparative LCMS to give the title compound.¹H NMR (CD₃OD) δ 7.74-7.78 (m, 1H), 7.43 (t, J=3.7 Hz, 1H), 7.41 (t,J=3.6 Hz, 1H), 7.36 (s, 1H), 7.28-7.31(m, 1H), 7.20 (d, J=8.1 Hz, 1H),6.96 (t, J=7.2 Hz, 1H), 6.67 (t, J=7.2 Hz, 1H), 6.48 (d, J=7.8 Hz, 1H),4.62 (s, 2H), 2.78 (s, 3H); MS: ESI (negative): 319 (M−H).

EXAMPLE 21[3-(1-Benzyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid a.) 5-Chloro-3-(6-chloro-pyridazin-3-yl)-2-methyl-1H-indole (Scheme3)

The sub-title compound was prepared using 1,4-dichloropyridazine asdescribed for example 16, step a). MS: ESI (negative): 276, 278 (M−H).

b.) [5-Chloro-3-(6-chloro-pyridazin-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared from the product of step a) usingthe procedure described in example 15, step b). MS: ESI (positive): 392,394 (M+H).

c.) [5-Chloro-3-(6-hydroxy-pyridazin-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The sub-title compound was prepared from the product of step b) usingthe procedure described in example 16, step c). The reaction was heatedovernight. MS: ESI (negative): 372, 374 (M−H).

d.)[3-(1-Benzyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid

The title compound was prepared from the product of step c) using theprocedure described in example 14, step d). ¹H NMR (DMSO-d₆) δ 7.75 (d,J=9.6 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.39 (s,1H), 7.38 (d, J=1.8 Hz, 1H), 7.35-7.30 (m, 1H), 7.15 (dd, J=8.1, 2.1 Hz,1H), 7.07 (d, J=9.6 Hz, 1H), 5.35 (s, 2H), 5.07 (s, 2H), 2.41 (s, 3H);MS: ESI (negative): 406, 408 (M−H).

EXAMPLE 22{3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-indol-1-yl}-aceticacid a.) 2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-isoindole-1,3-dione(Scheme 4)

4-Chloromethyl-3,5-dimethyl-isoxazole (500 μL, 3.40 mmol) was added to amixture of phthalimide (500 mg, 3.40 mmol) and K₂CO₃ (500 mg, 3.62 mmol)in DMF (5 mL) and stirred at ambient temperature overnight. The reactionwas then heated to 70° C. for 5 hours and subsequently cooled andpartitioned between ethyl acetate and water. The organic layer waswashed several times with water and concentrated to give 1.0 g of thesub-title compound as a white solid. MS: ESI (positive): 257 (M+H).

b.)2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-hydroxy-2,3-dihydro-isoindol-1-one

NaBH₄ (36 mg, 0.938 mmol) was added slowly to a stirring mixture of2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-isoindole-1,3-dione (20 mg, 0.781mmol) in methanol (2 mL). After stirring at room temperature for 10minutes, the reaction was quenched with acetic acid (1 mL) andpartitioned between water and dichloromethane. The organic layer waswashed several times with water and concentrated under vacuum to givethe sub-title compound as a white solid. MS: ESI (positive): 259 (M+H).

c.)2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-(1H-indol-3-yl)-2,3-dihydro-isoindol-1-one

The product of step b) was treated according to the conditions describedin example 22, step b). The product was purified by chromatography(EtOAc/Hex) to give the sub-title compound as a brown oil. MS: ESI(positive): 358 (M+H).

d.){3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-indol-1-yl}-aceticacid

The title-compound was prepared from the product of step c) as describedfor example 22, step c). MS: ESI (negative): 414 (M−H).

EXAMPLE 23{2-Methyl-3-[2-(3-methyl-butyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-indol-1-yl}-aceticacid

(Scheme 2)

The title compound was prepared from the product of example 19, step a)and 1-bromo-3-methyl-butane using the procedure described in example 17,step d). ¹H NMR (DMSO-d₆) δ 8.09 (d, J=7.2 Hz, 1H), 7.90 (t, J=7.5 Hz,1H), 7.81 (t, J=7.8 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.38 (d, J=8.1 Hz,1H), 7.19 (d, J=7.8 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 4.52 (s, 2H), 3.89(t, J=6.9 Hz, 2H), 1.90 (s, 3H), 1.74 (q, J=6.9 Hz, 2H), 1.64 (sept.,J=6.7 Hz, 1H), 0.92 (d, J=6.3 Hz, 6H); MS: ESI (negative): 438 (M−H).

EXAMPLE 24{5-Chloro-3-[3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-1-yl]-2-methyl-indol-1-yl}-aceticacid

(Scheme 3)

The title compound was prepared from the product of example 16, step c)and 4-fluorobenzyl bromide using the procedure described in example 14.¹H NMR (DMSO-d₆) δ 13.25 (bs, 1H), 8.41 (d, J=6.6 Hz, 1H), 7.94-7.87 (m,2H), 7.58 (d, J=8.7 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.45 (dd, J=5.7,8.4 Hz, 2H), 7.24-7.10 (m, 4H), 5.44 (d, J=14.4 Hz, 1H), 5.38 (d, J=14.4Hz, 1H), 5.14 (s, 2H), 2.24 (s, 3H); MS: ESI (negative): 474, 476 (M−H).

EXAMPLE 25(5-Chloro-3-{3-[2-(4-chloro-phenoxy)-ethyl]-4-oxo-3,4-dihydro-phthalazin-1-yl}-2-methyl-indol-1-yl)-aceticacid

(Scheme 3)

The title compound was prepared from the product of example 16, step c)and 1-(2-bromo-ethoxy)-4-chloro-benzene using the procedure described inexample 14. MS: ESI (negative): 520, 522 (M−H).

EXAMPLE 26[3-(3-Benzothiazol-2-ylmethyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid

(Scheme 3)

The title compound was prepared from the product of example 16, step c)and 2-chloromethyl-benzothiazole using the procedure described inexample 14. ¹H NMR (DMSO-d₆) δ 8.44-8.41 (m, 1H), 8.08 (d, J=8.1 Hz,1H), 7.99 (d, J=8.1 Hz, 1H), 7.96-7.92 (m, 2H), 7.50 (t, J=7.5 Hz, 1H),7.44 (t, J=7.5 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.15 (dd, J=8.7, 2.1 Hz,1H), 5.86 (s, 2H), 5.12 (s, 2H), 2.28 (s, 3H); MS: ESI (negative): 513,515 (M−H).

EXAMPLE 27{5-Chloro-3-[3-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-oxo-3,4-dihydro-phthalazin-1-yl]-2-methyl-indol-1-yl}-aceticacid

(Scheme 3)

The title compound was prepared from the product of example 16, step c)and 2-chloromethyl-2,3-dihydro-benzo[1,4]dioxine using the proceduredescribed in example 14. MS: ESI (negative): 514, 516 (M−H).

EXAMPLE 28[3-(2-Benzyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using benzyl bromide. ¹H NMR (DMSO-d₆) δ 7.99 (d, J=8.7 Hz, 1H),7.66-7.57 (m, 2H), 7.43 (s, 1H), 7.31-7.22 (m, 5H), 7.17 (d, J=7.5 Hz,1H), 7.04 (t, J=7.6 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.80 (t, J=7.5 H,1H), 5.76 (s, 1H), 4.53 (s, 2H), 4.55 (d, J=15.9 Hz, 1H), 3.93 (d,J=15.9 Hz, 1H); MS: ESI (negative): 431 (M−H).

EXAMPLE 29{3-[2-(3-Methyl-butyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using isoamyl bromide. MS: ESI (negative): 411 (M−H).

EXAMPLE 30[3-(1,1-Dioxo-2-quinolin-2-ylmethyl-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using 2-bromomethyl-quinoline. MS: ESI (negative): 482 (M−H).

EXAMPLE 31(3-{2-[3-(4-Fluoro-phenoxy)-benzyl]-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl}-indol-1-yl)-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using 3-(4-fluorophenoxy)benzyl bromide. MS: ESI (negative): 541 (M−H).

EXAMPLE 32[3-(2-Biphenyl-2-ylmethyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using o-phenylbenzyl bromide. MS: ESI (negative): 507 (M−H).

EXAMPLE 33{3-[1,1-Dioxo-2-(2-thiophen-2-yl-thiazol-4-ylmethyl)-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-indol-1-yl}-acetic acid

(Scheme 1)

The title compound was prepared by the method described for example 14using 4-chloromethyl-2-thiophen-2-yl-thiazole. MS: ESI (negative): 520(M−H).

EXAMPLE 34(3-{2-[2-(4-Chloro-phenyl)-thiazol-4-ylmethyl]-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl}-indol-1-yl)-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using 4-chloromethyl-2-(4-chloro-phenyl)-thiazole. ¹H NMR (DMSO-d₆)13.05 (bs, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H),7.67-7.61 (m, 2H), 7.60 (s, 1H), 7.54 (s, 1H), 7.50 (d, J=8.1 Hz, 2H),7.37 (d, J=8.4 Hz, 1H), 7.21-7.18 (m, 1H), 7.08 (t, J=7.6 Hz, 1H), 7.02(d, J=7.8 Hz, 1H), 6.86 (t, J=7.5 Hz, 1H), 6.19 (s, 1H), 5.01 (s, 2H),4.62 (d, J=16.5 Hz, 1H), 4.21 (d, J=16.5 Hz, 1H); MS: ESI (negative):548, 550 (M−H).

EXAMPLE 35{3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-indol-1-yl}-aceticacid

(Scheme,1)

The title compound was prepared by the method described for example 14using 4-chloromethyl-3,5-dimethyl-isoxazole. MS: ESI (negative): 450(M−H).

EXAMPLE 36{2-Methyl-3-[2-(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and4-chloromethyl-5-methyl-3-phenyl-isoxazole. MS: ESI (negative): 526(M−H).

EXAMPLE 37(3-{2-[(4-Fluoro-phenylcarbamoyl)-methyl]-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl}-2-methyl-indol-1-yl)-acetic acid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) andalpha-chloro-4-fluoroacetanilide. ¹H NMR (DMSO-d₆) δ 8.06-8.03 (m, 1H),7.70-7.62 (m, 2H), 7.51-7.46 (m, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.17-7.13(m, 2H), 7.02 (t, J=8.1 Hz, 1H), 6.80 (t, J=7.5 Hz, 1H), 6.72 (bs, 1H),6.55 (s, 1H), 5.00 (s, 2H), 4.15 (d, J=17.4 Hz, 1H), 3.40 (d, J=17.4 Hz,1H), 2.39 (s, 3H); MS: ESI (negative): 506 (M−H).

EXAMPLE 38{3-[2-(2-Hydroxy-ethyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-2-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and 2-bromoethanol. ¹H NMR(DMSO-d₆) δ 7.98-7.95 (m, 1H), 7.62-7.58 (m, 3H), 7.36 (d, J=8.4 Hz,1H), 7.04-7.01 (m, 2H), 6.80-6.78 (m, 1H), 6.14 (s, 1H), 5.00 (s, 2H),4.75 (bs, 1H), 3.59-3.53 (m, 1H), 3.26-3.17 (m, 2H), 3.02-2.92 (m, 1H),2.39 (s, 3H); MS: ESI (negative): 399 (M−H).

EXAMPLE 39(3-{2-[2-(4-Chloro-phenoxy)-ethyl]-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl}-2-methyl-indol-1-yl)-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and1-(2-bromo-ethoxy)-4-chloro-benzene. MS: ESI (negative): 509 (M−H).

EXAMPLE 40[3-(2-Ethoxycarbonylmethyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and ethyl bromoacetate. MS:ESI (negative): 441 (M−H).

EXAMPLE 41{3-[2-(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-2-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and2-bromomethyl-2,3-dihydro-benzo[1,4]dioxine. MS: ESI (negative): 503(M−H).

EXAMPLE 42{2-Methyl-3-[2-(2-methyl-thiazol-4-ylmethyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and4-chloromethyl-2-methyl-thiazole. ¹H NMR (DMSO-d₆) δ 13.04 (bs, 1H),8.00 (d, J=8.7 Hz, 1H), 7.66-7.58 (m, 2H), 7.37 (d, J=8.1 Hz, 1H), 7.19(s, 1H), 7.08 (d, J=6.3 Hz, 1H), 7.01 (t, J=7.8 Hz, 1H), 6.87-6.76 (m,2H), 6.18 (s, 1H), 5.00 (s, 2H), 4.51 (d, J=16.2 Hz, 1H), 3.92 (d,J=16.2 Hz, 1H), 2.58 (s, 3H), 2.31 (s, 3H); MS: ESI (negative): 466(M−H).

EXAMPLE 43{3-[1,1-Dioxo-2-(3-trifluoromethyl-benzyl)-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-2-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and 3-trifluoromethyl-benzylbromide. MS: ESI (negative): 513 (M−H).

EXAMPLE 44{2-Methyl-3-[2-(3-methyl-butyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and 1-iodo-3-methyl-butane.MS: ESI (negative): 425 (M−H).

EXAMPLE 45[3-(2-Allyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and allyl bromide. MS: ESI(negative): 395 (M−H).

EXAMPLE 46{3-[1,1-Dioxo-2-(3-phenoxy-propyl)-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-2-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and (3-bromo-propoxy)-benzene.MS: ESI (negative): 489 (M−H).

EXAMPLE 47[3-(2-Isopropyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 3, step c) and 2-iodo propane. ¹H NMR(DMSO-d₆) δ 7.91-7.88 (m, 1H), 7.63-7.53 (m, 2H), 7.35 (d, J=8.4 Hz,1H), 7.17-6.78 (m, 4H), 6.14 (s, 1H), 4.98 (s, 2H), 3.68 (sept., J=6.8Hz, 1H), 2.43 (s, 3H), 1.34 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.9 Hz, 3H);MS: ESI (negative): 397 (M−H).

EXAMPLE 48[3-(2-Benzothiazol-2-ylmethyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-methyl-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 2, step c) and2-bromomethyl-benzothiazole. MS: ESI (negative): 502 (M−H).

EXAMPLE 49{3-[2-(4-Fluoro-benzyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-5-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 2, step c) and 4-fluorobenzyl bromide. ¹HNMR (DMSO-d₆) 8.00 (d, J=6.6 Hz, 1H), 7.66-7.58 (m, 2H), 7.39 (s, 1H),7.24 (dd, J=3.0, 8.4 Hz, 2H), 7.22-7.20 (m, 1H), 7.04 (t, J=8.8 Hz, 2H),6.90 (d, J=8.1 Hz, 1H), 6.76 (s, 1H), 5.75 (s, 1H), 4.94 (s, 2H), 4.50(d, J=15.9 Hz, 1H), 3.97 (d, J=15.9 Hz, 1H), 2.16 (s, 3H); MS: ESI(negative): 463 (M−H).

EXAMPLE 50{3-[2-(3-Benzyloxy-propyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-5-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 2, step c) and(3-bromo-propoxymethyl)-benzene. MS: ESI (negative): 503 (M−H).

EXAMPLE 51{3-[1,1-Dioxo-2-(3-trifluoromethyl-benzyl)-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-5-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 2, step c) and 3-trifluoromethyl benzylbromide. MS: ESI (negative): 513 (M−H).

EXAMPLE 52{3-[2-(3-Methoxy-propyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-5-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 2, step c) and 3-bromo-1-methoxy propane.¹H NMR (DMSO-d₆) 7.95-7.92 (m, 1H), 7.60 (d, J=3.6 Hz, 1H), 7.58 (s,1H), 7.28 (d, J=8.1 Hz, 1H), 7.12-7.09 (m, 1H), 7.02 (t, J=7.2 Hz, 1H),6.97 (d, J=8.4 Hz, 1H), 6.79 (t, J=7.5 Hz, 1H), 5.89 (s, 1H), 4.57 (s,2H), 3.44-3.03 (m, 4H), 3.01 (s, 3H), 2.45 (s, 3H), 1.71 (quint., J=6.6Hz, 2H); MS: ESI (negative): 427 (M−H).

EXAMPLE 53{3-[2-(Cyano-methyl-methyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-5-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 2, step c) and 2-bromo-propionitrile. MS:ESI (negative): 408 (M−H).

EXAMPLE 54{3-[2-(4-Fluoro-benzyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-5-methoxy-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 4, step c) and 4-fluorobenzyl bromide.MS: ESI (negative): 479 (M−H).

EXAMPLE 55[3-(1,1-Dioxo-2-phenethyl-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-methoxy-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 4, step c) and 2-bromoethylbenzene. ¹HNMR (DMSO-d₆) 13.03 (bs, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.65-7.60 (m, 2H),7.50 (s, 1H), 7.29 (d, J=9.0 Hz, 1H), 7.25-7.13 (m, 4H), 7.09 (d, J=8.1Hz, 2H), 6.74 (dd, J=2.4, 9.0 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 5.95 (s,1H), 5.00 (s, 2H), 3.51 (s, 3H), 3.42 (ddd, J=6.3, 10.2, 15.9 Hz, 1H),3.14 (ddd, J=5.7, 9.9, 15.0 Hz, 1H), 3.00-2.70 (m, 2H); MS: ESI(negative): 475 (M−H).

EXAMPLE 56{5-Methoxy-3-[2-(1-methyl-2-phenyl-ethyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 4, step c) and (2-bromo-propyl)-benzene.MS: ESI (negative): 489 (M−H).

EXAMPLE 57{3-[2-(4-Cyano-benzyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-5-methoxy-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 4, step c) and 4-cyanobenzyl bromide. MS:ESI (negative): 486 (M−H).

EXAMPLE 58[3-(2-Allyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 6, step c) and allyl bromide. ¹H NMR(DMSO-d₆) 13.14 (bs, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.67-7.59 (m, 2H),7.45 (d, J=8.7 Hz, 1H), 7.06 (d, J=6.3 Hz, 1H), 7.02 (dd, J=1.8, 8.7 Hz,1H), 6.83 (s, 1H), 5.96 (s, 1H), 5.82-5.69 (m, 1H), 5.14 (d, J=7.5 Hz,1H), 5.10 (s, 1H), 5.03 (s, 2H), 3.90 (dd, J=4.8, 15.9 Hz, 1H),3.45-3.36 (m, 1H), 2.37 (s, 3H); MS: ESI (negative): 429, 431 (M−H).

EXAMPLE 59[5-Chloro-3-(2-ethoxycarbonylmethyl-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 6, step c) and ethyl bromoacetate. ¹H NMR(DMSO-d₆) 13.15 (bs, 1H), 8.07-8.03 (m, 1H), 7.70-7.63 (m, 2H), 7.44 (d,J=8.7 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 7.02 (dd, J=1.8, 8.7 Hz, 1H),6.72 (s, 1H), 6.28 (s, 1H), 5.03 (s, 2H), 4.05-3.92 (m, 2H), 3.41 (q,J=6.9 Hz, 2H), 1.05 (t, J=6.9 Hz, 3H); MS: ESI (negative): 475, 477(M−H).

EXAMPLE 60{5-Chloro-3-[2-(4-fluoro-benzyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-2-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 6, step c) and 4-fluorobenzyl bromide. ¹HNMR (DMSO-d₆) 13.2 (bs, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.67 (t, J=7.2 Hz,1H), 7.62 (dt, J=1.5, 7.5 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.19-6.96 (m,6H), 6.83 (s, 1H), 5.83 (s, 1H), 5.01 (d, J=18.3 Hz, 1H), 5.00 (d,J=18.3 Hz, 1H), 4.50 (d, J=15.6 Hz, 1H), 3.83 (d, J=15.6 Hz, 1H), 2.11(s, 3H); MS: ESI (negative): 497, 499 (M−H).

EXAMPLE 61{5-Chloro-2-methyl-3-[2-(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 6, step c) and4-chloromethyl-5-methyl-3-phenyl-isoxazole. ¹H NMR (DMSO-d₆) 7.99-7.91(m, 1H), 7.69-7.60 (m, 2H), 7.43 (d, J=8.7 Hz, 1H), 7.36 (d, J=7.2 Hz,2H), 7.23-6.75 (m, 6H), 5.94 (s, 1H), 4.96 (s, 2H), 4.33 (d, J=14.1 Hz,1H), 4.07 (d, J=14.1 Hz, 1H), 3.30 (s, 3H), 2.41 (s, 3H); MS: ESI(negative): 560, 562 (M−H).

EXAMPLE 62{3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-6-fluoro-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-2-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 13, step e) andchloromethyl-3,5-dimethyl-isoxazole. ¹H NMR (DMSO-d₆) δ 13.1 (bs, 1H),7.99 (dd, J=2.4, 7.5 Hz, 1H), 7.47 (dt, J=2.1, 8.8 Hz, 1H), 7.14-6.74(m, 4H), 5.93 (s, 1H), 5.01 (s, 2H), 4.02 (d, J=15 Hz, 1H), 3.98 (d, 1H,J=15 Hz, 1H), 2.40 (s, 3H), 2.04 (s, 3H), 1.71 (s, 3H); MS: ESI(negative): 482 (M−H).

EXAMPLE 63{3-[6-Fluoro-2-(3-fluoro-benzyl)-1,1-dioxo-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl]-2-methyl-indol-1-yl}-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 13, step e) and 4-fluorobenzyl bromide.¹H NMR (DMSO-d₆) δ 13.2 (bs, 1H), 8.11 (dd, J=2.4, 7.5 Hz, 1H), 7.50(dt, J=2.4, 8.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.32-6.77 (m, 8H), 5.89(s, 1H), 5.00 (d, J=18 Hz, 1H), 4.98 (d, J=18 Hz, 1H), 4.56 (d, J=15.9Hz, 1H), 3.81 (d, J=15.9 Hz, 1H), 2.11 (s, 3H); MS: ESI (negative): 481(M−H).

EXAMPLE 64[3-(6-Fluoro-1,1-dioxo-2-phenethyl-2,3-dihydro-1H-1λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid

(Scheme 1)

The title compound was prepared by the method described for example 14using the product from example 13, step e) and 2-phenethyl bromide. MS:ESI (negative): 477 (M−H).

EXAMPLE 65{3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-methyl-1,1-dioxo-2,3-dihydro-1H-λ⁶-benzo[d]isothiazol-3-yl]-2-methyl-indol-1-yl}-aceticacid a.)[2-Methyl-3-(3-methyl-1,1-dioxo-2,3-dihydro-1H-λ⁶-benzo[d]isothiazol-3-yl)-indol-1-yl]-aceticacid tert-butyl ester (Scheme 5)

The product of example 3, step b) (1.0 g, 2.44 mmol) was dissolved in 40mL toluene and cooled to 0° C. Me₃Al (1.83 mL of 2 M solution intoluene) was slowly added and the reaction was stirred for 45 minutes at0° C. MeMgBr (3.5 mL of 1.4 M solution) was added and the reaction wasallowed to warm to rt. The reaction was quenched with saturated NH₄Clthen partitioned between water and EtOAc. The organic layer was driedover MgSO₄ and the crude product was purified by silica gelchromatography (EtOAc/Hex) to give 450 mg of the sub-title compound.

b.){3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-methyl-1,1-dioxo-2,3-dihydro-1H-λ⁶-benzo[d]isothiazol-3-yl]-2-methyl-indol-1-yl}-aceticacid

The product of step a) (50 mg, 0.12 mmol) was dissolved in 2 mL of DMFand treated with 0.24 mmol (35 mg) of4-chloromethyl-3,5-dimethyl-isoxazole and 0.23 mmol (32 mg) of K₂CO₃.The reaction was heated to 80° C. for 1 h then diluted with EtOAc (5 mL)and was washed 3× with water. The organic layer was concentrated andsubsequently treated with EtOH (5 mL) and 1M NaOH (1 mL). The reactionwas heated to 75° C. for 2h, cooled to rt, acidified with 1M HCl (3 mL)and extracted 3× into DCM. The combined extracts were concentrated andpurified by preparative LCMS to give the title compound. ¹H NMR(DMSO-d₆) δ 7.81 (dd, J=3.6, 5.7 Hz, 1H), 7.56 (dt, J=3.0, 8.7 Hz, 2H),7.28 (d, J=8.1 Hz, 1H), 7.14-7.11 (m, 2H), 7.00 (t, J=7.2 Hz, 1H), 6.80(t, J=7.2 Hz, 1H), 4.64 (s, 2H), 4.01 (d, J=14.7 Hz, 1H), 3.89 (d,J=14.7 Hz, 1H), 2.10 (s, 3H), 1.91 (s, 3H), 1.89 (s, 3H), 1.80 (s. 3H);MS: ESI (negative): 478.6 (M−H).

EXAMPLE 66{3-[2-(3-Fluoro-benzyl)-3-methyl-1,1-dioxo-2,3-dihydro-1H-λ⁶-benzo[d]isothiazol-3-yl]-2-methyl-indol-1-yl}-aceticacid

(Scheme 5)

The product of example 65, step a) (50 mg, 0.12 mmol) was dissolved in 2mL DMF and treated with K₂CO₃ (32 mg, 0.23 mmol) and3-fluoro-benzylbromide (43 mg, 0.23 mmol). After heating to 75° C. for 2h, the reaction was cooled, diluted with EtOAc, and washed 3× H₂O. Theorganic solution was concentrated and treated with 3 mL TFA for 2 h atrt. The reaction was concentrated and the title compound was isolated bypreparative LCMS to give the title compound. MS: ESI (negative): 477.5(M−H).

EXAMPLE 67{2-Methyl-3-[3-methyl-1,1-dioxo-2-(2-phenoxy-ethyl)-2,3-dihydro-1H-λ⁶-benzo[d]isothiazol-3-yl]-indol-1-yl}-aceticacid

(Scheme 5)

The title compound was prepared by the method described in example 66using (2-bromo-ethoxy)-benzene. MS: ESI (negative): 489.7 (M−H).

EXAMPLE 68{3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2-methyl-indol-1-yl}-aceticacid a.)2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-(2-methyl-1H-indol-3-yl)-2,3-dihydro-isoindol-1-one(Scheme 4)

The product of example 22, step b) (230 mg, 0.89 mmol) was treated with2-methyl indole (196 mg, 1.5 mmol) and heated (neat) to 180° C. for 1 h.The reaction was cooled and the sub-title product was purified by silicachromatography (EtOAc/Hex).

b.){3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2-methyl-indol-1-yl}-aceticacid tert-butyl ester

The product from step a) (100 mg, 0.3 mmol) was dissolved in DMF (4 mL)and treated with t-butyl bromoacetate (112 mg, 0.6 mmol) and K₂CO₃ (103mg, 0.75 mmol). After heating to 70° C. for 14 h, the reaction wasdiluted with DCM and washed repeatedly with water. Concentration gave110 mg of the sub-title compound which was used without furtherpurification.

c.){3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-2-methyl-indol-1-yl}-aceticacid

The crude product of step b) was dissolved in 3 mL EtOH and treated with0.5 mL of 1 M NaOH. After heating to 70° C. for 1 h, the reaction wascooled, acidified with 1 M HCl and extracted into DCM. The extracts wereconcentrated and the title compound was purified by preparative LCMS togive the title compound. ¹H NMR (DMSO-d₆) δ 7.84-7.81 (m, 1H), 7.56-7.46(m, 2H), 7.25 (d, J=8.1 Hz, 1H), 7.19-7.16 (m, 1H), 6.93 (t, J=7.5 Hz,1H), 6.69 (t, J=7.5 Hz, 1H), 6.39 (d, J=7.8 Hz, 1H), 3.73 (s, 1H), 4.85(d, J=15.2 Hz, 1H), 4.52 (d, J=17.1 Hz, 1H), 4.51 (d, J=17.1 Hz, 1H),3.51 (d, J=15.3 Hz, 1H), 2.35 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H); MS:ESI (negative): 428.6 (M−H).

EXAMPLE 69{3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1,1-dioxo-λ⁶-isothiazolidin-3-yl]-2-methyl-indol-1-yl}-aceticacid a.) (3-Formyl-2-methyl-indol-1-yl)-acetic acid tert-butyl ester(Scheme 6)

K₂CO₃ (15 mmol, 2.07g) and 1-formyl-2-methyl indole (10 mmol, 1.59 g)were stirred in 50 mL DMF. t-Butyl bromoacetate (12 mmol, 1.77 mL) wasadded and the reaction was heated to 80° C. for 1 h. The reaction wascooled, diluted with 100 mL EtOAc, and washed with water (3×50 mL). Theorganic solution was dried over MgSO₄ and concentrated to give thesub-title compound as a yellow solid (2.6 g).

b.){2-Methyl-3-[(2-phenyl-ethenesulfonylimino)-methyl]-indol-1-yl}-aceticacid tert-butyl ester

The product of step a) (1.5 g, 5.5 mmol), 2-phenyl-ethenesulfonic acidamide (1.0 g, 5.5 mmol), and PPTS (75 mg) were treated with 500 mLtoluene and heated to reflux overnight in a flask equipped with aDean-Stark trap. The hot reaction mixture was decanted and allowed tocool. The resulting precipitate was filtered and washed with toluene togive 1.86 g of the sub-title compound as a white solid.

c.){2-Methyl-3-[1-(2-phenyl-ethenesulfonylamino)-allyl]-indol-1-yl}-aceticacid tert-butyl ester

The product of step b) (2.2 g, 5 mmol) was treated with 100 mL toluene.The slurry was stirred at 0° C. and treated with Me₃Al (3.8 mL of 2 M intoluene) followed by vinyl magnesium bromide (10 mL of 1 M). Thereaction was warmed to rt and stirred for 10 minutes. The reaction wascooled to 0° C., quenched with aqueous acetic acid, and partitionedbetween water and EtOAc (200 mL each). The organic layer was washed with1 M NaOH, dried over MgSO₄ and purified over silica gel (30% EtOAc/Hex)to give 1.25 g of the sub-title compound as an oil.

d.)[3-(1,1-Dioxo-2,3-dihydro-1H-λ⁶-isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The product of step c) (1.26 g, 2.7 mmol) was dissolved in 300 mL DCMunder an Ar atmosphere. Grubbs catalyst (2^(nd) generation, 154 mg, 0.19mmol) was added and the solution was heated to reflux for 3 h. Thereaction was concentrated and the sub-title compound was purified bysilica gel chromatography (EtOAc/Hex) to give 0.80 g of the sub-titlecompound as a dark oil.

e.) [3-(1,1-Dioxo-λ⁶-isothiazolidin-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

The product of step d) (65 mg, 0.18 mmol) was dissolved in 4 mLisopropanol and treated with NaBH₄ (7 mg, 0.18 mmol). The reaction washeated to 80° C. for 2 h, after which time an additional 7 mg of NaBH₄was added. Heating was continued for 1 h. The reaction was quenched withHOAc and partitioned between DCM and water. The organic layer was washedwith water and concentrated to give 58 mg of crude sub-title compoundwhich was used without further purification.

f.){3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1,1-dioxo-λ⁶-isothiazolidin-3-yl]-2-methyl-indol-1-yl}-aceticacid

The product of step e) (58 mg, 0.16 mmol) was dissolved in DMF (3 mL)and treated with K₂CO₃ (44 mg, 0.32 mmol) and4-chloromethyl-3,5-dimethyl-isoxazole (0.32 mmol, 47 mg). After heatingto 80° C. for 2 h, the reaction was diluted with EtOAc and washed 3×with water. The organic layer was concentrated and treated with EtOH (3mL) and 1 M NaOH (0.7 mL). After heating to 80° C. for 1 h the reactionwas concentrated to dryness and purified by preparative LCMS to give thetitle compound. ¹H NMR (DMSO-d₆) δ 7.70 (d, J=7.2 Hz, 1H), 7.33 (d,J=8.1 Hz, 1H), 7.07 (t, J=7.5 Hz, 1H), 6.98 (t, J=7.3 Hz, 1H), 4.77 (s,2H), 4.61 (dd, 1H, J=6.3, 10.2 Hz), 3.72 (s, 2H), 3.57 (dd, 1H, J=7.2,12.3 Hz), 3.25-3.05 (m, 1H), 2.62-2.25 (m, 2H), 2.21 (s, 3H), 1.88 (s,3H); MS: ESI (negative): 416.8 (M−H).

EXAMPLE 70[3-(3-Butyl-4-oxo-3,4,4a,5,8,8a-hexahydro-phthalazin-1-yl)-2-methyl-indol-1-yl]-aceticacid a.) 6-(2-Methyl-1H-indole-3-carbonyl)-cyclohex-3-enecarboxylic acid(Scheme 7)

2-Methyl indole (50 mmol, 6.55 g) and AlCl₃ (50 mmol, 7.3 g) werestirred in 500 mL DCE. cis-1,2,3,6-Tetrahydrophthalic anhydride (50mmol, 7.6 g) was added and the reaction was heated to 65° C. for 6 h.The reaction was carefully quenched with 10 mL water and stirredovernight. The resulting red solid was filtered, washed with water, anddried to give 15 g of the sub-title compound.

b.)2-Butyl-4-(2-methyl-1H-indol-3-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

The product of step a) (200 mg, 0.71 mmol) was treated with Et₃N (0.71mmol, 98 uL), n-butyl hydrazine oxalate (0.71 mmol, 126 mg) and 10 mLtoluene. The suspension was refluxed for 48 h. The reaction was cooled,treated with 15 mL EtOAc and 5 mL 1M NaOH, and heated to 70° C. for 30min. The organic layer was filtered through silica gel and furthereluted with EtOAc. The combined eluent was concentrated to dryness togive the sub-titled compound which was used without furtherpurification.

c.)[3-(3-Butyl-4-oxo-3,4,4a,5,8,8a-hexahydro-phthalazin-1-yl)-2-methyl-indol-1-yl]-aceticacid

The product of step b) was dissolved in DMF (4 mL) and treated withK₂CO₃ (0.7 mmol, 97 mg) and t-butyl bromoacetate (0.5 mmol, 74 uL).After heating at 75° C. for 2 h, the reaction was cooled, diluted withEtOAc (10 mL) and washed 3× water. The organic solution was concentratedto dryness and treated with 4 mL TFA for 1.5 h. The reaction wasconcentrated and the title compound was purified by preparative LCMS. ¹HNMR (DMSO-d₆) δ 7.76 (d, J=8.1 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H),7.09-6.99 (m, 2H), 5.70 (d, J=10.8 Hz, 1H), 5.63 (d, J=10.8 Hz, 1H),3.91 (dt, J=6.9, 13.2 Hz, 1H), 3.62 (dt, J=6.6, 13.2 Hz, 1H), 3.36(quint., J=5.7 Hz, 1H), 2.96 (t, J=5.1 Hz, 1H), 2.79-2.71 (m, 1H),2.35-1.94 (m, 4H), 1.64 (quint., J=7.1 Hz, 2H), 1.31 (sext., J=7.5 Hz,1H), 0.91 (t, J=7.2 Hz, 3H); MS: ESI (negative): 392 (M−H).

EXAMPLE 71[3-(3-Benzyl-4-oxo-3,4,4a,5,8,8a-hexahydro-phthalazin-1-yl)-2-methyl-indol-1-yl]-aceticacid

(Scheme 7)

The title compound was prepared by the method described for example 70except using benzyl hydrazine hydrochloride in step b). ¹H NMR (DMSO-d₆)δ7.67 (d, J=7.8Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.37-7.26 (m, 5H), 7.12(t, J=7.5 Hz, 1H), 7.03 (t, J=7.5, 1H), 5.71 (d, J=12 Hz, 1H), 5.61 (d,J=12 Hz, 1H), 5.15 (d, J=14.7 Hz, 1H), 5.01 (s, 2H), 4.81 (d, J=14.7 Hz,1H), 3.11 (t, J=5.6 Hz, 1H), 2.81-2.75 (m, 1H), 2.35 (s, 3H), 2.35-2.18(m, 2H), 2.07-1.88 (m, 2H); MS: ESI (positive): 428.8 (M+H).

EXAMPLE 72[2-Methyl-3-(4-oxo-3-phenethyl-3,4,4a,5,8,8a-hexahydro-phthalazin-1-yl)-indol-1-yl]-aceticacid

(Scheme 7)

The title compound was prepared by the method described for example 70except using phenethyl hydrazine sulfuric acid salt in step b). ¹H NMR(DMSO-d₆) δ 7.73 (d, J=6.9 Hz, 1H), 7.35-7.14 (m, 7H), 7.08 (t, J=6.4Hz, 1H), 7.03 (t, J=6.4 Hz, 1H), 5.66 (d, J=11.1 Hz, 1H), 5.55 (d,J=11.1 Hz, 1H), 4.47 (s, 2H), 4.18 (dt, J=7.2, 13.2 Hz, 1H), 3.88 (dt,J=6.9, 13.5 Hz, 1H), 3.32 (quint., J=5.4 Hz, 1H), 2.99 (t, J=7.2 Hz,1H), 2.93 (t, J=5.6 Hz, 1H), 2.76-2.66 (m, 1H), 2.45 (s, 3H), 2.24-1.97(m, 4H); MS: ESI (negative): 440.8 (M−H).

EXAMPLE 73[3-(1-Benzyl-5,5-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid a.) 4-(5-Chloro-2-methyl-1H-indol-3-yl)-2,2-dimethyl-4-oxo-butyricacid (Scheme 7)

3,3-Dimethyl-dihydro-furan-2,5-dione (7.8 mmol, 1.0 g),5-chloro-2-methylindole (13.8 mmol, 2.28 g), and AlCl₃ (9.0 mmol, 1.2 g)were stirred in 100 mL DCE overnight at 65° C. The reaction was cooledand quenched with 10 mL water. The resultant precipitate was filteredand washed with a small amount of DCE giving 1.06 g of the sub-titledcompound.

b.)2-Benzyl-6-(5-chloro-2-methyl-1H-indol-3-yl)-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one

The product of step a) (0.5 mmol, 147 mg) was treated with toluene (10mL), benzyl hydrazine dihydrochloride (0.7 mmol, 136 mg) and Et₃N (1.3mmol, 181 uL). The reaction was refluxed overnight then cooled to rt.Filtration through a pad of silica gel followed by elution with EtOAcgave the sub-title compound.

c.)[3-(1-Benzyl-5,5-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid

The product of step b) (˜0.3 mmol) was dissolved in 5 mL DMF and treatedwith K₂CO₃ (1 mmol, 138 mg) and t-butyl bromoacetate (1 mmol, 195 mg).After heating to 80° C. for ½ h, the reaction was cooled, diluted withEtOAc and washed 5× water. The reaction was concentrated, dissolved inEtOH (5 mL) and treated with 1.4 mL of 1M NaOH. After heating to 80° C.for ½ h, the reaction was acidified with 3 M HCl and extracted into DCM(3×). The title product was purified by preparative LCMS. ¹H NMR(DMSO-d₆) δ 7.65 (d, J=2.4 Hz, 1H), 7.48-7.30 (m, 6H), 7.12 (dd, J=6.6,2.4 Hz, 1H), 5.04 (s, 2H), 4.94 (s, 2H), 2.96 (s, 2H), 2.38 (s, 3H),1.12 (s, 6H); MS: ESI (negative): 436 (M−H).

EXAMPLE 74[3-(1,1-Dioxo-2-phenyl-2,3-dihydro-1H-λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid a.)[3-(1,1-Dioxo-2-phenyl-2,3-dihydro-1H-λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid tert-butyl ester (Scheme 1)

The product of example 3, step c) (150 mg, 0.36 mmol) was dissolved intoluene (8 mL) and treated with CuI (69 mg, 0.36 mmol), N,N′-dimethylethylenediamine (77 uL, 0.72 mmol), bromobenzene (85 mg, 0.54 mmol), andK₂CO₃ (149 mg, 1.1 mmol). The reaction was heated to reflux for 3 days.Upon cooling, the reaction was filtered and concentrated to give thecrude product which was used without further purification.

b.)[3-(1,1-Dioxo-2-phenyl-2,3-dihydro-1H-λ⁶-benzo[d]isothiazol-3-yl)-2-methyl-indol-1-yl]-aceticacid

The crude product from step a) (73 mg, 0.15 mmol) was dissolved in 8 mLEtOH and treated with 1 mL of 1 M NaOH. After heating to 80° C. for 2 h,the reaction was acidified with aqueous HCl and extracted into DCM (2×5mL). The title compound was purified by preparative LCMS. ¹H NMR(DMSO-d₆) δ 8.09-8.06 (m, 1H), 7.72-7.65 (m, 2H), 7.46-7.26 (m, 5H),7.17 (t, J=7.3 Hz, 1H), 7.13-7.09 (m, 2H), 6.97 (t, J=7.0 Hz, 1H),6.91-6.77 (m, 2H), 5.05 (s, 2H); MS: ESI (positive): 434.5 (M+H).

EXAMPLE 75[3-(2-Benzyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid a.)4-(5-Fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide. (Scheme 2)

AlCl₃ (1.2 g, 10.5 mmol) was added to a solution of4-chloro-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (1.5 g, 7.0 mmol) and5-fluoro-2-methyl indole (1.0 g, 7.0 mmol) in DCE (35 mL), and stirredovernight at 70° C. The reaction solution was diluted with H₂O, and theproduct was extracted with a solution of CH₂Cl₂/EtOH (9/1, v/v). Theextracted product was concentrated and purified via silica gelchromatography eluting with a gradient of 0 to 70% EtOAc in hexanes toafford 0.44 g (19%) of the sub-title compound. MS calculated forC₁₆H₁₂FN₃O₂S—H: 328, observed: 328.

b.)[3-(2-Benzyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester

Benzyl bromide (10 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) were added toa solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

c.)[3-(2-Benzyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid

{[3-(2-Benzyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.14 (d, 1H), 7.92 (t, 1H), 7.81 (t, 1H),7.46 (d, 1H), 7.38 (m, 6H), 6.88 (dt, 1H), 6.61 (dd, 1H), 4.96 (s, 2H),4.49 (s, 2H), 2.08 (s, 3H) ppm. MS calculated for C₂₅H₂₀FN₃O₄S—H: 476,observed: 476.

EXAMPLE 76{3-[2-(2-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(2-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

2-Chlorobenzyl chloride (9 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) wereadded to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(2-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(2-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.18 (d, 1H), 7.94 (t, 1H), 7.83 (t, 1H),7.45 (m, 6H), 6.88 (dt, 1H), 6.51 (dd, 1H), 5.19 (bs, 2H), 4.43 (s, 2H),2.02 (s, 3H) ppm. MS calculated for C₂₅H₁₉FClN₃O₄S—H: 510, observed:510.

EXAMPLE 77{3-[2-(3-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(3-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

3-Chlorobenzyl chloride (9 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) wereadded to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(3-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(3-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.18 (d, 1H), 7.92 (t, 1H), 7.84 (t, 1H),7.45 (m, 6H), 6.90 (dt, 1H), 6.61 (dd, 1H), 5.10 (bs, 2H), 4.52 (s, 2H),2.09 (s, 3H) ppm. MS calculated for C₂₅H₁₉FClN₃O₄S—H: 510, observed:510.

EXAMPLE 78{3-[2-(4-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(4-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

4-Chlorobenzyl chloride (11 mg, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) wereadded to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(4-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(4-Chloro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.15 (d, 1H), 7.91 (t, 1H), 7.82 (t, 1H),7.45 (m, 6H), 6.89 (dt, 1H), 6.60 (dd, 1H), 5.08 (bs, 2H), 4.59 (s, 2H),2.08 (s, 3H) ppm. MS calculated for C₂₅H₁₉FClN₃O₄S—H: 510, observed:510.

EXAMPLE 79{3-[2-(3-Methoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(3-Methoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

3-Methoxybenzyl chloride (10 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol)were added to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(3-Methoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(3-Methoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.13 (d, 1H), 7.91 (t, 1H), 7.84 (t, 1H),7.48 (d, 1H), 7.38 (dd, 1H), 7.28 (t, 1H), 6.91 (m, 4H), 6.69 (dd, 1H),5.06 (bs, 2H), 4.51 (s, 2H), 3.71 (s, 3H), 2.11 (s, 3H) ppm. MScalculated for C₂₆H₂₂FN₃O₅S—H: 506, observed: 506.

EXAMPLE 80{3-[2-(4-Methoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(4-Methoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

4-Methoxybenzyl chloride (10 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol)were added to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(4-Methoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(4-Methoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.12 (d, 1H), 7.91 (t, 1H), 7.81 (t, 1H),7.44 (d, 1H), 7.32 (m, 3H), 6.92 (m, 3H), 6.62 (dd, 1H), 4.99 (bs, 2H),4.51 (s, 2H), 3.73 (s, 3H), 2.09 (s, 3H) ppm. MS calculated forC₂₆H₂₂FN₃O₅S—H: 506, observed: 506.

EXAMPLE 81{3-[2-(2-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(2-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

2-Fluorobenzyl bromide (8 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) wereadded to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(2-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(2-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 7.94 (d, 1H), 7.72 (t, 1H), 7.63 (t, 1H),7.22 (d, 4H), 7.02 (m, 2H), 6.69 (dt, 1H), 6.38 (dd, 1H), 4.92 (bs, 2H),4.51 (s, 2H), 1.86 (s, 3H) ppm. MS calculated for C₂₅H₁₉F₂N₃O₄S—H: 494,observed: 494.

EXAMPLE 82{3-[2-(3-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(3-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

3-Fluorobenzyl bromide (8 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) wereadded to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(3-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(3-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.17 (d, 1H), 7.95 (t, 1H), 7.86 (t, 1H),7.42 (m, 3H), 7.19 (m, 3H), 6.89 (dt, 1H), 6.61 (dd, 1H), 5.09 (bs, 2H),4.53 (s, 2H), 2.09 (s, 3H) ppm. MS calculated for C₂₅H₁₉F₂N₃O₄S—H: 494,observed: 494.

EXAMPLE 83{3-[2-(4-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(4-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

4-Fluorobenzyl bromide (8 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) wereadded to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(4-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(4-Fluoro-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.15 (d, 1H), 7.93 (t, 1H), 7.84 (t, 1H),7.47 (m, 3H), 7.38 (dd, 1H), 7.21 (m, 2H), 6.89 (dt, 1H), 6.57 (dd, 1H),5.09 (bs, 2H), 4.51 (s, 2H), 2.09 (s, 3H) ppm. MS calculated forC₂₅H₁₉F₂N₃O₄S—H: 494, observed: 494.

EXAMPLE 84{3-[2-(4-Trifluoromethoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(4-Trifluoromethoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

4-Trifluoromethoxybenzyl bromide (11 μL, 67 μmol) and K₂CO₃ (10 mg, 72μmol) were added to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(4-Trifluoromethoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(4-Trifluoromethoxy-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.17 (d, 1H), 7.93 (t, 1H), 7.85 (t, 1H),7.50 (m, 3H), 7.38 (m, 3H), 6.89 (dt, 1H), 6.59 (dd, 1H), 5.11 (bs, 2H),4.52 (s, 2H), 2.08 (s, 3H) ppm. MS calculated for C₂₆H₁₉F₄N₃O₅S—H: 560,observed: 560.

EXAMPLE 85{3-[2-(3-Trifluoromethyl-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.)(3-[2-(3-Trifluoromethyl-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

3-Trifluoromethylbenzyl bromide (10 μL, 67 μmol) and K₂CO₃ (10 mg, 72μmol) were added to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(3-Trifluoromethyl-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(3-Trifluoromethyl-benzyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.18 (d, 1H), 7.95 (t, 1H), 7.86 (t, 1H),7.70 (m, 4H), 7.48 (d, 1H), 7.37 (dd, 1H), 6.89 (dt, 1H), 6.52 (dd, 1H),5.18 (bs, 2H), 4.48 (s, 2H), 2.07 (s, 3H) ppm. MS calculated forC₂₆H₁₉F₄N₃O₄S—H: 544, observed: 544.

EXAMPLE 86{3-[2-(1-phenyl-ethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(1-phenyl-ethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

(1-Bromoethyl)benzene (9 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) wereadded to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(1-phenyl-ethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(1-Phenyl-ethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.11 (d, 1H), 7.91 (t, 1H), 7.81 (t, 1H),7.36 (m, 8H), 6.91 (m, 1H), 5.72 (m, 1H), 4.52 (s, 2H), 2.07 (s, 3H),1.85 (d, 3H) ppm. MS calculated for C₂₆H₂₂FN₃O₄S—H: 490, observed: 490.

EXAMPLE 87{3-[2-phenethyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-phenethyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

(2-Bromoethyl)benzene (9 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) wereadded to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-phenethyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-Phenethyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.07 (d, 1H), 7.89 (t, 1H), 7.83 (t, 1H),7.45 (m, 2H), 7.20 (m, 5H), 6.91 (m, 2H), 4.56 (s, 2H), 4.11 (t, 2H),3.12 (t, 2H), 2.21 (s, 3H) ppm. MS calculated for C₂₆H₂₂FN₃O₄S—H: 490,observed: 490.

EXAMPLE 88{3-[2-(2-Phenoxy-ethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(2-Phenoxy-ethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

β-Bromophenetole (14 mg, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) were addedto a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(2-Phenoxy-ethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(2-Phenoxy-ethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.12 (d, 1H), 7.92 (t, 1H), 7.82 (t, 1H),7.46 (m, 2H), 7.22 (m, 2H), 6.96 (m, 5H), 4.58 (s, 2H), 4.39 (t, 2H),4.28 (t, 2H), 2.21 (s, 3H) ppm. MS calculated for C₂₆H₂₂FN₃O₅S—H: 506,observed: 506.

EXAMPLE 89(3-{2-[2-(4-Chloro-phenoxy)-ethyl]-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl}-5-fluoro-2-methyl-indol-1-yl)-aceticacid a.)(3-{2-[2-(4-Chloro-phenoxy)-ethyl]-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl}-5-fluoro-2-methyl-indol-1-yl)-aceticacid tert-butyl ester (Scheme 2)

4-Chlorophenyl 2-bromoethyl ether (16 mg, 67 μmol) and K₂CO₃ (10 mg, 72μmol) were added to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.)(3-{2-[2-(4-Chloro-phenoxy)-ethyl]-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl}-5-fluoro-2-methyl-indol-1-yl)-aceticacid

(3-{2-[2-(4-Chloro-phenoxy)-ethyl]-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl}-5-fluoro-2-methyl-indol-1-yl)-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.11 (d, 1H), 7.92 (t, 1H), 7.83 (t, 1H),7.46 (m, 2H), 7.24 (m, 2H), 6.95 (m, 4H), 4.52 (s, 2H), 4.39 (t, 2H),4.27 (t, 2H), 2.20 (s, 3H) ppm. MS calculated for C₂₆H₂₁FClN₃O₅S—H: 540,observed: 540.

EXAMPLE 90{3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid a.){3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (Scheme 2)

4-Chloromethyl-3,5-dimethylisoxazole (8 μL, 67 μmol) and K₂CO₃ (10 mg,72 μmol) were added to a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.){3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid

{3-[2-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl]-5-fluoro-2-methyl-indol-1-yl}-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 7.99 (d, 1H), 7.78 (t, 1H), 7.70 (t, 1H),7.30 (d, 1H), 7.27 (dd, 1H), 6.79 (dt, 1H), 6.62 (dd, 1H), 4.71 (s, 2H),4.39 (s, 2H), 2.23 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H) ppm. MScalculated for C₂₄H₂₁FN₄O₅S—H: 495, observed: 495.

EXAMPLE 91 [3-(2-Ethyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid a.)[3-(2-Ethyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester (Scheme 2)

Iodoethane (5 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) were added to asolution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.)[3-(2-Ethyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid

[3-(2-Ethyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.09 (d, 1H), 7.91 (t, 1H), 7.84 (t, 1H),7.48 (d, 1H), 7.42 (dd, 1H), 6.97 (m, 2H), 4.52 (s, 2H), 3.96 (q, 2H),2.21 (s, 3H), 1.39 (t, 3H) ppm. MS calculated for C₂₀H₁₈FN₃O₄S—H: 414,observed: 414.

EXAMPLE 92[3-(2-Propyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid a.)[3-(2-Propyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester (Scheme 2)

1-Iodopropane (7 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) were added to asolution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.)[3-(2-Propyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid

[3-(2-Propyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.10 (d, 1H), 7.91 (t, 1H), 7.84 (t, 1H),7.47 (m, 2H), 6.97 (m, 2H), 4.57 (s, 2H), 3.86 (t, 2H), 2.23 (s, 3H),1.84 (m, 2H), 0.92 (t, 3H) ppm. MS calculated for C₂₁H₂₀FN₃O₄S—H: 428,observed: 428.

EXAMPLE 93[3-(2-Isopropyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid a.)[3-(2-Isopropyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester (Scheme 2)

2-Iodopropane (7 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) were added to asolution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.)[3-(2-Isopropyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid

[3-(2-Isopropyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.08 (d, 1H), 7.90 (t, 1H), 7.83 (t, 1H),7.47 (m, 2H), 6.97 (m, 2H), 4.71 (m, 1H), 4.53 (s, 2H), 2.23 (s, 3H),1.47 (m, 6H) ppm. MS calculated for C₂₁H₂₀FN₃O₄S—H: 428, observed: 428.

EXAMPLE 94[3-(2-Cyclohexyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid a.)[3-(2-Cyclohexyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester (Scheme 2)

Cyclohexyl bromide (8 μL, 67 μmol) and K₂CO₃ (10 mg, 72 μmol) were addedto a solution of4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine1,1-dioxide (20 mg, 61 μmol) in CH₃CN (1 mL), and stirred overnight at80° C. An additional amount of K₂CO₃ (10 mg, 72 μmol) and tert-butylbromoacetate (14 μL, 92 μmol) was added, and the reaction mixturestirred an additional 2 h at 80° C. The reaction mixture was dilutedwith H₂O and CH₂Cl₂, and filtered through an Extrelut column. TheExtrelut column was washed with CH₂Cl₂, and the filtrate wasconcentrated to afford the sub-title compound, which was carried ontothe next step without further purification or characterization.

b.)[3-(2-Cyclohexyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid

[3-(2-Cyclohexyl-1,1-dioxo-1,2-dihydro-1λ⁶-benzo[e][1,2,3]thiadiazin-4-yl)-5-fluoro-2-methyl-indol-1-yl]-aceticacid tert-butyl ester (61 μmol) was treated with TFA (2 mL) for 2 hours,concentrated, and purified by preparative LCMS to give the titlecompound. ¹H NMR (d₆-DMSO) δ 8.08 (d, 1H), 7.88 (t, 1H), 7.81 (t, 1H),7.42 (m, 2H), 6.91 (m, 2H), 4.55 (s, 2H), 4.29 (m, 1H), 2.23 (s, 3H),1.88 (m, 5H), 1.65 (m, 2H), 1.47 (m, 2H), 1.11 (m, 1H) ppm. MScalculated for C₂₄H₂₄FN₃O₄S—H: 468, observed: 468.

EXAMPLE 95 CRTH-2 Binding Assay

A CRTH2 binding assay was developed to measure the ability of compoundsto inhibit the binding of PGD₂ to human CRTH2 using a scintillationproximity assay.

Membranes containing hCRTH2 receptors were prepared from HEK293EBNA-hCRTH2 cells (a HEK 293EBNA cell line stably expressing humanCRTH2). The cells were grown to confluency, harvested and washed withPBS. The cells were resuspended in 10 mM Hepes pH 7.4, 1 mM EDTA andprotease inhibitors and incubated for 30 min on ice. The cells werehomogenized and centrifuged for 10 min at 1000×g. The supernate wascentrifuged for 30 min at 100,000×g and the membrane pellet was thenresusupended in 10 mM Hepes pH 7.4 and 1 mM EDTA. The proteinconcentration of the membrane preparation was determined by Bradfordassay (Bio-Rad).

The ability of compounds to inhibit the interaction of PGD₂ to humanCRTH2 was determined at seven compound concentrations. Compounds wereserially diluted in DMSO then diluted into CRTH2 buffer without glycerol(10 mM Hepes pH 7.4, 1 mM EDTA, 10 mM MnCl₂) to six times the finaldesired concentration. 20 μL of the diluted compounds were transferredinto non-surface binding 96 well plates (Corning). Each concentrationwas done in triplicate. In addition to test compounds, each platecontained 12 control wells. Six of these wells contained 20 μL of CRTH2buffer without glycerol. These wells were used to measure total binding.Six wells contained 20 μL of CRTH2 buffer without glycerol plus 1.5 mMindomethacin. These wells were used to measure non-specific binding.Next, HEK 293EBNA-hCRTH2 membranes were resuspended in CRTH2 buffer withglycerol (10 mM Hepes pH 7.4, 1 mM EDTA, 10 mM MnCl₂, 25% glycerol) sothat the final concentration was approximately 20 μg protein/100 μL.Polylysine coated yttrium silicate SPA beads (Amersham) were added tothe membrane mix to a concentration of 0.4 mg/100 μL and finally ³H-PGD₂was added to the membrane/SPA bead mix to 3.6 nM. 100 μL of themembrane/SPA bead/³H—PGD₂ mix was added to each well of the non-surfacebinding plates containing the diluted compound plus controls. The plateswere incubated for 2 hours at room temperature with shaking and then theplates were counted on a Microbeta scintillation counter (Perkin Elmer)for 1 min per well.

IC₅₀ values were determined from the experimental results by nonlinearregression using Prism 4.0 software. The IC₅₀ values were then used inconjunction with the K_(d) for hCRTH2 and the ³H-PGD₂ concentration usedin the experiment to calculate the K_(i) for each compound. The resultsare shown in Table 1.

TABLE 1 Ex Ki No. Compound (μM) 1

<10 2

<10 3

<10 4

<10 5

<10 6

<1 7

<10 8

<10 9

<10 10

<1 11

<1 12

<1 13

<1 14

<10 15

<1 16

<0.1 17

<1 18

<10 19

<0.1 20

>10 21

<0.1 22

<1 23

<0.1 24

<0.1 25

<0.1 26

<0.1 27

<0.1 28

<10 29

<10 30

<10 31

<1 32

<1 33

<1 34

<1 35

<0.1 36

<0.1 37

<10 38

<10 39

<0.1 40

<1 41

<1 42

<1 43

<1 44

<1 45

<1 46

<1 47

<1 48

<1 49

<1 50

<10 51

<10 52

<10 53

<10 54

<1 55

<10 56

<10 57

<10 58

<1 59

<0.1 60

<1 61

<0.1 62

<0.1 63

<1 64

<0.1 65

<0.1 66

<1 67

<1 68

<1 69

<0.1 70

<1 71

<1 72

<0.1 73

<0.1 74

<1 75

<1 76

<0.1 77

<1 78

<1 79

<1 80

<0.1 81

<0.1 82

<0.1 83

<0.1 84

<1 85

<1 86

<0.1 87

<1 88

<1 89

<1 90

<0.1 91

<0.1 92

<0.1 93

<0.1 94

<0.1

EXAMPLE 96 CRTH2 Fluorescent Imaging Assay

The ability of the disclosed compounds to act as agonists for the hCRTH2receptor was determined by their ability to cause increases inintracellular calcium via binding to the CRTH2 receptor. The compoundswere also tested for their ability to act as antagonists for the hCRTH2receptor as measured by the ability of the compounds to block theincrease in intracellular calcium normally caused by PGD₂ binding to theCRTH2 receptor.

Assays were performed on HEK 293EBNA-hCRTH2 cells that had been grown inDMEM media containing 10% FBS, 3 μL/mL puromycin and 1%penicillin/streptomycin/glutamine (PSG) at 37° C. in 5% CO₂ or onHT1080-hCRTH2 cells (a HT1080 cell line stably expressing human CRTH2)that had been grown in alphaMEM media containing 10% FBS, 500 μg/mlhygromycin, 200 nM methotrexate and 1% PSG at 37° C. in 5% CO₂.

For the assay, HEK 293EBNA-hCRTH2 cells or HT1080-hCRTH2 cells weregrown to approximately 90% confluency and then dislodged from the platewith Trypsin-EDTA, resuspended in DMEM media, seeded in 384 well platesat 2×10⁴ cells per well and incubated overnight at 37° C. The cells wereloaded with a calcium sensing dye by removing the growth media andreplacing it with 30 μL of dye loading Ringer's buffer (136 mM CsCl, 5.4mM D-Glucose, 20 mM Hepes pH 7.4, 2.1 mM MgCl₂, 0.8 mM CaCl₂, 0.2% BSAwith 1× Calcium3Dye (Molecular Devices) and 2.5 mM Probenecid (Sigma))per well. The cells were incubated at 37° C. for 1 hour to allow the dyeto enter the cells. Compounds were serially diluted in DMSO and thendiluted to 4× their final concentration with Ringer's buffer. Thecompounds were added to a 384 well plate in quadruplicate. In additionto test compounds, several wells contained Ringer's buffer with DMSO.These wells serve as control wells. 10 μL was transferred fromcompound/control plate to the plate containing cells loaded with dye bya fluorescent imaging plate reader (Molecular Devices). The fluorescencewas measured every 4 seconds for 4 minutes. These measurements indicatedthe level of intracellular calcium. Increases in fluorescence relativeto wells containing buffer only indicated an agonist effect of thecompound. Measurement at various compound concentrations allowed one todetermine the EC₅₀ for these compounds. Following the 4 minuteincubation with compound, 20 μL of Ringer's buffer with either 10 nM or500 nM PGD₂ (approximate EC₇₅ for PGD₂ in HEK 293EBNA-hCRTH2 cells andHT1080-hCRTH2 cells, respectively) was added to the wells. Inhibition bythe compounds of the calcium response due to antagonism of PGD₂ actionon CRTH2 is reflected by a decrease in fluorescent signal relative towells containing no compound. The fluorescence was measured every 2seconds for 10 seconds before addition of PGD₂ and every 2 seconds for110 seconds following addition. Measurement at various compoundconcentrations allowed one to determine the IC₅₀ for these compounds.EC₅₀ and IC₅₀ values were determined from the experimental results bynonlinear regression using the Prism 4.0 software. The results are shownin Table 2.

TABLE 2 Example Number HT1080-hCRTH2 IC₅₀ (μM) 16 0.019 24 0.06 61 0.1762 0.022

Having now fully described the invention, it will be understood by thoseof skill in the art that the same can be performed within a wide andequivalent range of conditions, formulations, and other parameterswithout affecting the scope of the invention or any embodiment thereof.All patents, patent applications and publications cited herein are fullyincorporated by reference herein in their entirety.

1. A compound having Formula I:

or a pharmaceutically acceptable salt, ester or amide thereof, wheresaid ester is derived from a C₁₋₆ alcohol and said amide is derived froma C₁₋₆ amine, wherein: the dotted lines are single or double bonds; X isC═O; Z is N; R₁ is selected from H, optionally substituted C₁₋₁₀ alkyl,optionally substituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀alkynyl, optionally substituted C₁₋₁₀ alkylaryl, optionally substitutedC₁₋₁₀ alkylheteroaryl, optionally substituted —C₁₋₁₀ alkyl-O—C₁₋₁₀alkyl, optionally substituted —C₁₋₁₀ alkyl-O-aryl, optionallysubstituted —C₁₋₁₀ alkyl-O-heteroaryl, optionally substituted aryl, andoptionally substituted heteroaryl; R₂, R_(2a), R₃ and R_(3a) areindependently selected from H, halogen, and C₁₋₁₀ alkyl, wherein R_(2a)and R_(3a) are present only when the carbons to which they are attachedare saturated; or R₂ and R₃, taken together with the carbon atoms towhich they are attached, form an optionally substituted saturated,unsaturated, or aromatic 5- or 6-membered ring; or R₂ and R_(2a), takentogether with the carbon atoms to which they are attached, form anoptionally substituted saturated 3-6 membered ring; R₄ is H, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, or halogen, wherein R₄ is presentonly when the carbon to which it is attached is saturated; R₅ is H,C₁₋₁₀ alkyl, perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀alkylaryl, C₁₋₁₀ alkylheteroaryl, aryl, or heteroaryl, wherein said arylor heteroaryl is optionally substituted with one or more substituentsselected from C₁₋₁₀ alkyl, halogen, C₁₋₁₀ alkoxy, and CN; R₆ is one ormore H, halogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, CN, OR₇,SR₇, aryl or heteroaryl groups; and R₇ is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, aryl, or heteroaryl wherein unless otherwise specified,optional substituents are selected from C₁₋₁₀ alkyl, halogen, halo C₁₋₁₀alkyl, halo C₁₋₁₀ alkoxy, cycloalkyl, hydroxy, cyano, aryl, aryloxy,carbamoyl, aralkyl, heteroaryl, heteroaryloxy, alkoxycarbonyl, amino,acyloxy, arylacyloxy, heterocyclo, heterocycloalkoxy, partiallyunsaturated heterocyclylalkyl and partially unsaturatedheterocyclylalkoxy, and where each optional substituent may be furthersubstituted with one or more C₁₋₆ alkyl, halogen, halo C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, haloalkoxy, aryl, or heteroaryl groups.
 2. The compound ofclaim 1, or a pharmaceutically acceptable salt, ester or amide thereof,having Formula V:


3. A compound, which is:[3-(3-benzyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-indol-1-yl]-acetic acid;[3-(3-benzyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid;[3-(1-benzyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid;{5-chloro-3-[3-(4-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-1-yl}-2-methyl-indol-1-yl}-aceticacid;{5-chloro-3-[3-(4-chloro-phenoxy)-4-oxo-3,4-dihydro-phthalazin-1-yl}-2-methyl-indol-1-yl}-aceticacid;[3-(3-benzothiazol-2-ylmethyl-4-oxo-3,4-dihydro-phthalazin-1-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid;{5-chloro-3-[3-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-oxo-3,4-dihydro-phthalazin-1-yl]-2-methyl-indol-1-yl}-aceticacid;[3-(3-butyl-4-oxo-3,4,4a,5,8,8a-hexahydro-phthalazin-1-yl)-indol-1-yl]-aceticacid;[3-(3-benzyl-4-oxo-3,4,4a,5,8,8a-hexahydro-phthalazin-1-yl)-indol-1-yl]-aceticacid;[2-methyl-3-(4-oxo-3-phenethyl-3,4,4a,5,8,8a-hexahydro-phthalazin-1-yl)-indol-1-yl]-aceticacid; or[3-(1-benzyl-5,5-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-5-chloro-2-methyl-indol-1-yl]-aceticacid, or a pharmaceutically acceptable salt, ester or amide thereof,where said ester is derived from a C₁₋₆ alcohol and said amide isderived from a C₁₋₆ amine.
 4. The compound of claim 1, or apharmaceutically acceptable salt, ester or amide thereof, wherein: R₁ isselected from H, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₁₋₁₀ alkylaryl,optionally substituted C₁₋₁₀ alkylheteroaryl, optionally substituted—C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, optionally substituted —C₁₋₁₀ alkyl-O-aryl,and optionally substituted aryl; R₂, R_(2a), R₃, and R_(3a) are eachindependently selected from H, halogen, and C₁₋₁₀ alkyl, or R₂ and R₃,taken together with the carbon atoms to which they are attached, form anoptionally substituted saturated, unsaturated or aromatic 5- or6-membered ring; R₄ is H or C₁₋₁₀ alkyl; R₅ is H or C₁₋₁₀ alkyl; R₆ isone or more H, halogen, C₁₋₁₀ alkyl, CN, or OR₇ groups; and R₇ is H orC₁₋₁₀ alkyl.
 5. The compound of claim 4, or a pharmaceuticallyacceptable salt, ester or amide thereof, wherein R₁ is H, methyl, ethyl,propyl, butyl, isopropyl, isobutyl, cyclohexyl, allyl, phenyl, benzyl,carbamoylmethyl, ethoxycarbonylmethyl, benzothiazolylmethyl,benzodioxinylmethyl, isoxazolylmethyl, quinolinylmethyl,thiazolylmethyl, cyanoethyl, hydroxyethyl, phenethyl, phenoxyethyl,methoxypropyl, phenoxypropyl, or phenoxybenzyl.
 6. The compound of claim4, or a pharmaceutically acceptable salt, ester or amide thereof,wherein R₁ is propyl, benzyl, benzothiazolylmethyl, benzodioxinylmethyl,phenethyl, or phenoxyethyl.
 7. The compound of claim 4, or apharmaceutically acceptable salt, ester or amide thereof, wherein R₂,R_(2a), R₃, and R_(3a) are each independently selected from H, halogen,and C₁₋₁₀ alkyl.
 8. The compound of claim 4, or a pharmaceuticallyacceptable salt, ester or amide thereof, wherein R₂, R_(2a), R₃, andR_(3a) are each independently selected from H and methyl.
 9. Thecompound of claim 4, or a pharmaceutically acceptable salt, ester oramide thereof, wherein R₂ and R₃, taken together with the carbon atomsto which they are attached, form a saturated, unsaturated or aromatic 5-or 6-membered ring.
 10. The compound of claim 4, or a pharmaceuticallyacceptable salt, ester or amide thereof, wherein R₂ and R₃, takentogether with the carbon atoms to which they are attached, form abenzene or cyclohexene ring.
 11. The compound of claim 4, or apharmaceutically acceptable salt, ester or amide thereof, wherein R₄ isH or methyl.
 12. The compound of claim 4, or a pharmaceuticallyacceptable salt, ester or amide thereof, wherein R₅ is H or methyl. 13.The compound of claim 4, or a pharmaceutically acceptable salt, ester oramide thereof, wherein R₆ is H, methyl, cyano, methoxy, bromo, chloro,or fluoro.
 14. A pharmaceutical composition comprising a compound ofclaim 1, or a pharmaceutically acceptable salt, ester or amide thereof,and a pharmaceutically acceptable carrier.
 15. A pharmaceuticalcomposition comprising a compound of claim 4, or a pharmaceuticallyacceptable salt, ester or amide thereof, and a pharmaceuticallyacceptable carrier.
 16. A method of treating in a mammal, comprisingadministering to said mammal a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt, ester oramide thereof, wherein the disorder is selected from asthma, chronicobstructive pulmonary disease, bronchitis, rhinitis, nasal polyposis,sarcoidosis, farmer's lung, fibroid lung, idiopathic interstitialpneumonia, cystic fibrosis, cough, psoriasis, dermatitis, urticaria,cutaneous eosinophilias, food-related allergies, eosinophilia fascitisand hyper IgE syndrome.
 17. The method of claim 16, wherein saiddisorder is asthma, chronic obstructive pulmonary disease, bronchitis,rhinitis, nasal polyposis, sarcoidosis, farmer's lung, fibroid lung,idiopathic interstitial pneumonia, cystic fibrosis, or cough.
 18. Themethod of claim 16, wherein said disorder is psoriasis, dermatitis,urticaria or cutaneous eosinophilias.
 19. The method of claim 16,wherein said disorder is food-related allergies.
 20. The method of claim16, wherein said disorder is eosinophilia fascitis or hyper IgEsyndrome.
 21. The method of claim 16, further comprising administeringan additional therapeutic agent.
 22. A kit comprising a compound ofclaim 1, or a pharmaceutically acceptable salt, ester or amide thereof,and instructions for administering said compound, pharmaceuticallyacceptable salt, ester or amide to an animal.
 23. The kit of claim 22,further comprising an additional therapeutic agent.
 24. A method ofpreparing a compound having formula XXIV, comprising a) condensing acompound having formula VIII with a 1,4-dihalo phthalazine compound toform a compound having formula XXI;

b) condensing a compound having formula XXI with a halogenated aceticacid alkyl ester to form a compound having formula XXII;

c) hydrolyzing a compound having formula XXII to form a compound havingformula XXIII; and

d) alkylating or arylating a compound having formula XXIII followed bydeprotecting to form a compound having formula XXIV;

wherein R₁ is selected from H, optionally substituted C₁₋₁₀ alkyl,optionally substituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀alkynyl, optionally substituted C₁₋₁₀ alkylaryl, optionally substitutedC₁₋₁₀ alkylheteroaryl, optionally substituted —C₁₋₁₀ alkyl-O—C₁₋₁₀alkyl, optionally substituted —C₁₋₁₀ alkyl-O-aryl, optionallysubstituted —C₁₋₁₀ alkyl-O-heteroaryl, optionally substituted aryl, andoptionally substituted heteroaryl, where unless otherwise specified,optional substituents are selected from C₁₋₁₀ alkyl, halogen, halo C₁₋₁₀alkyl, halo C₁₋₁₀ alkoxy, cycloalkyl, hydroxy, cyano, aryl, aryloxy,carbamoyl, aralkyl, heteroaryl, heteroaryloxy, alkoxycarbonyl, amino,acyloxy, arylacyloxy, heterocyclo, heterocycloalkoxy, partiallyunsaturated heterocyclylalkyl and partially unsaturatedheterocyclylalkoxy, and where each optional substituent may be furthersubstituted with one or more C₁₋₆ alkyl, halogen, halo C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, haloalkoxy, aryl, or heteroaryl groups; R₅ is H, C₁₋₁₀alkyl, perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl,C₁₋₁₀ alkylheteroaryl, aryl, or heteroaryl, wherein said aryl orheteroaryl is optionally substituted with one or more substituentsselected from C₁₋₁₀ alkyl, halogen, C₁₋₁₀ alkoxy, and CN; R₆ is one ormore H, halogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, CN, OR₇,SR₇, aryl or heteroaryl groups; R₇ is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, aryl, or heteroaryl; R₈ is H, halo, C₁₋₁₀ alkoxy, cyano,C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀alkylheteroaryl, —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, —C₁₋₁₀ alkyl-O-aryl, —C₁₋₁₀alkyl-O-heteroaryl, aryl, or heteroaryl; Q is a halogen; and Y is aprotecting group.
 25. A method of preparing a compound having formulaXXIV, comprising alkylating or arylating a compound having formula XXIIIfollowed by deprotecting to form a compound having formula XXIV;

wherein R₁ is selected from H, optionally substituted C₁₋₁₀ alkyl,optionally substituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀alkynyl, optionally substituted C₁₋₁₀ alkylaryl, optionally substitutedC₁₋₁₀ alkylheteroaryl, optionally substituted —C₁₋₁₀ alkyl-O—C₁₋₁₀alkyl, optionally substituted —C₁₋₁₀ alkyl-O-aryl, optionallysubstituted —C₁₋₁₀ alkyl-O-heteroaryl, optionally substituted aryl, andoptionally substituted heteroaryl, where unless otherwise specified,optional substituents are selected from C₁₋₁₀ alkyl, halogen, halo C₁₋₁₀alkyl, halo C₁₋₁₀ alkoxy, cycloalkyl, hydroxy, cyano, aryl, aryloxy,carbamoyl, aralkyl, heteroaryl, heteroaryloxy, alkoxycarbonyl, amino,acyloxy, arylacyloxy, heterocyclo, heterocycloalkoxy, partiallyunsaturated heterocyclylalkyl and partially unsaturatedheterocyclylalkoxy, and where each optional substituent may be furthersubstituted with one or more C₁₋₆ alkyl, halogen, halo C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, haloalkoxy, aryl, or heteroaryl groups; R₅ is H, C₁₋₁₀alkyl, perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl,C₁₋₁₀ alkylheteroaryl, aryl, or heteroaryl, wherein said aryl orheteroaryl is optionally substituted with one or more substituentsselected from C₁₋₁₀ alkyl, halogen, C₁₋₁₀ alkoxy, and CN; R₆ is one ormore H, halogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, CN, OR₇,SR₇, aryl or heteroaryl groups; R₇ is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, aryl, or heteroaryl; R₈ is H, halo, C₁₋₁₀ alkoxy, cyano,C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀alkylheteroaryl, —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, —C₁₋₁₀ alkyl-O-aryl, —C₁₋₁₀alkyl-O-heteroaryl, aryl, or heteroaryl; and Y is a protecting group.26. A method of preparing a compound having formula XLII, comprising a)acylating an indole compound having formula VIII with a compound havingformula XXXIX to form a compound having formula XL;

b) cyclizing a compound having formula XL with an alkylhydrazide to forma compound having formula XLI; and

c) alkylating a compound having formula XLI with a halogenated aceticacid alkyl ester followed by deprotecting to form a compound havingformula XLII;

wherein R₁ is selected from H, optionally substituted C₁₋₁₀ alkyl,optionally substituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀alkynyl, optionally substituted C₁₋₁₀ alkylaryl, optionally substitutedC₁₋₁₀ alkylheteroaryl, optionally substituted —C₁₋₁₀ alkyl-O—C₁₋₁₀alkyl, optionally substituted —C₁₋₁₀ alkyl-O-aryl, optionallysubstituted —C₁₋₁₀ alkyl-O-heteroaryl, optionally substituted aryl, andoptionally substituted heteroaryl, where unless otherwise specified,optional substituents are selected from C₁₋₁₀ alkyl, halogen, halo C₁₋₁₀alkyl, halo C₁₋₁₀ alkoxy, cycloalkyl, hydroxy, cyano, aryl, aryloxy,carbamoyl, aralkyl, heteroaryl, heteroaryloxy, alkoxycarbonyl, amino,acyloxy, arylacyloxy, heterocyclo, heterocycloalkoxy, partiallyunsaturated heterocyclylalkyl and partially unsaturatedheterocyclylalkoxy, and where each optional substituent may be furthersubstituted with one or more C₁₋₆ alkyl, halogen, halo C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, haloalkoxy, aryl, or heteroaryl groups; R₂, R_(2a), and R₃are independently selected from H, halogen, and C₁₋₁₀ alkyl, whereinR_(2a) are present only when the carbons to which it is attached issaturated; or R₂ and R₃, taken together with the carbon atoms to whichthey are attached, form an optionally substituted saturated,unsaturated, or aromatic 5- or 6-membered ring, wherein optionalsubstituents are selected from C₁₋₁₀ alkyl, halogen, C₁₋₁₀ alkoxy, andCN; or R₂ and R_(2a), taken together the carbon atoms to which they areattached, form an optionally substituted saturated 3-6 membered ring,wherein optional substituents are selected from C₁₋₁₀ alkyl, halogen,C₁₋₁₀ alkoxy, and CN; R₅ is H, C₁₋₁₀ alkyl, perhaloalkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀ alkylheteroaryl, aryl, orheteroaryl, wherein said aryl or heteroaryl is optionally substitutedwith one or more substituents selected from C₁₋₁₀ alkyl, halogen, C₁₋₁₀alkoxy, and CN; and R₆ is one or more H, halogen, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, CN, OR₇, SR₇, aryl or heteroaryl groups; and R₇is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, or heteroaryl.27. A method of preparing a compound having formula XLII, comprisingcondensing a compound having formula XLI with a halogenated acetic acidalkyl ester followed by deprotecting to form a compound having formulaXLII;

wherein R₁ is selected from H, optionally substituted C₁₋₁₀ alkyl,optionally substituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀alkynyl, optionally substituted C₁₋₁₀ alkylaryl, optionally substitutedC₁₋₁₀ alkylheteroaryl, optionally substituted —C₁₋₁₀ alkyl-O—C₁₋₁₀alkyl, optionally substituted —C₁₋₁₀ alkyl-O-aryl, optionallysubstituted —C₁₋₁₀ alkyl-O-heteroaryl, optionally substituted aryl, andoptionally substituted heteroaryl, where unless otherwise specified,optional substituents are selected from C₁₋₁₀ alkyl, halogen, halo C₁₋₁₀alkyl, halo C₁₋₁₀ alkoxy, cycloalkyl, hydroxy, cyano, aryl, aryloxy,carbamoyl, aralkyl, heteroaryl, heteroaryloxy, alkoxycarbonyl, amino,acyloxy, arylacyloxy, heterocyclo, heterocycloalkoxy, partiallyunsaturated heterocyclylalkyl and partially unsaturatedheterocyclylalkoxy, and where each optional substituent may be furthersubstituted with one or more C₁₋₆ alkyl, halogen, halo C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, haloalkoxy, aryl, or heteroaryl groups; R₂, R_(2a), and R₃are independently selected from H, halogen, and C₁₋₁₀ alkyl, whereinR_(2a) are present only when the carbons to which it is attached issaturated; or R₂ and R₃, taken together with the carbon atoms to whichthey are attached, form an optionally substituted saturated,unsaturated, or aromatic 5- or 6-membered ring, wherein optionalsubstituents are selected from C₁₋₁₀ alkyl, halogen, C₁₋₁₀ alkoxy, andCN; or R₂ and R_(2a), taken together with the carbon atoms to which theyare attached, form an optionally substituted saturated 3-6 memberedring, wherein optional substituents are selected from C₁₋₁₀ alkyl,halogen, C₁₋₁₀ alkoxy, and CN; R₅ is H, C₁₋₁₀ alkyl, perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ alkylaryl, C₁₋₁₀ alkylheteroaryl, aryl, orheteroaryl, wherein said aryl or heteroaryl is optionally substitutedwith one or more substituents selected from C₁₋₁₀ alkyl, halogen, C₁₋₁₀alkoxy, and CN; and R₆ is one or more H, halogen, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, CN, OR₇, SR₇, aryl or heteroaryl groups; and R₇is H, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, aryl, or heteroaryl.28. The method of claim 16, wherein the mammal is a human, and whereinthe compound administered is a compound having Formula I:

or a pharmaceutically acceptable salt, ester or amide thereof, wherein:X is C═O; Z is N; R₁ is selected from H, optionally substituted C₁₋₁₀alkyl, optionally substituted C₂₋₁₀ alkenyl, optionally substitutedC₁₋₁₀ alkylaryl, optionally substituted C₁₋₁₀ alkyheteroaryl, optionallysubstituted —C₁₋₁₀ alkyl-O—C₁₋₁₀ alkyl, optionally substituted —C₁₋₁₀alkyl-O-aryl, and optionally substituted aryl; R₂, R_(2a), R₃, andR_(3a) are each independently selected from H, halogen, and C₁₋₁₀ alkyl,or R₂ and R₃, taken together with the carbon atoms to which they areattached, form an optionally substituted saturated, unsaturated oraromatic 5- or 6-membered ring; R₄ is H or C₁₋₁₀ alkyl; R₅ is H or C₁₋₁₀alkyl; R₆ is one or more H, halogen, C₁₋₁₀ alkyl, CN, or OR₇ groups; andR₇ is H or C₁₋₁₀ alkyl.
 29. The method of claim 28, wherein the disorderis asthma, chronic obstructive pulmonary disease, bronchitis, rhinitis,nasal polyposis, sarcoidosis, farmer's lung, fibroid lung, idiopathicinterstitial pneumonia, cystic fibrosis, or cough.
 30. The method ofclaim 28, wherein the disorder is asthma or chronic obstructivepulmonary disease.